WO2010146391A1 - Synthèse régiosélective de létrozole - Google Patents

Synthèse régiosélective de létrozole Download PDF

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Publication number
WO2010146391A1
WO2010146391A1 PCT/GB2010/050993 GB2010050993W WO2010146391A1 WO 2010146391 A1 WO2010146391 A1 WO 2010146391A1 GB 2010050993 W GB2010050993 W GB 2010050993W WO 2010146391 A1 WO2010146391 A1 WO 2010146391A1
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Prior art keywords
letrozole
methyl
salt
process according
iii
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PCT/GB2010/050993
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English (en)
Inventor
Vinayak Govind Gore
Vinay Kumar Shukla
Sheryas Bhandari
Suresh Hasbe
Sandeep Mekde
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Generics [Uk] Limited
Mylan India Private Limited
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Publication of WO2010146391A1 publication Critical patent/WO2010146391A1/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 an improved process for the preparation of letrozole (I) and its pharmaceutically acceptable salts, to compositions comprising letrozole or a pharmaceutically acceptable salt thereof, and to uses of such compositions.
  • it relates to a process and to novel intermediates for preparing letrozole and its salts substantially free from regioisomeric impurities.
  • Letrozole (I) chemically named as 4-[l-(4-cyanophenyl)-l-(l,2,4-triazol-l- yl)methyl]benzonitrile, is one of a new class of drugs, known as aromatase inhibitors, which function by reducing body levels of oestrogen in postmenopausal women. Many breast cancers increase in size by utilising the hormone oestrogen. In women who have undergone menopause, the main source of oestrogen is through changing androgens (sex hormones produced by the adrenal glands) into oestrogen, which is catalysed by an enzyme called aromatase.
  • the conversion process is known as aromatisation and happens mainly in the fatty tissues of the body. Letrozole blocks this aromatisation process and reduces the amount of oestrogen in the body and, consequently, letrozole is marketed as a type of hormonal therapy that is used in the treatment of breast cancer in women who have undergone menopause.
  • letrozole T
  • letrozole and processes to prepare it were first described in patent US 4,978,672.
  • the synthesis of letrozole proceeded via treatment of intermediate 4-[l-(l,2,4-triazol-l- yl) methyl] benzonitrile (III) with 4-fluorobenzonitrile (IV) in the presence of a catalyst, potassium tert-butoxide.
  • the preparation of intermediate (III) was achieved by reaction of ⁇ -bromotolunitrile with 1 ,2,4-triazole in a mixture of chloroform and acetonitrile at reflux, followed by the purification of the product (III) by column chromatography.
  • letrozole As the commercial production of letrozole is of great importance and in view of the above disadvantages associated with the prior art, there is a real need for alternative and improved processes for the preparation of letrozole which do not involve multiple steps and further eliminate the need for cumbersome purification techniques, particularly for the removal of the regioisomers (II) and (V).
  • the alternative processes must be economical and high yielding and provide letrozole with a high degree of chemical purity.
  • the object of the invention is to provide a process for the preparation of letrozole which eliminates formation of the regioisomeric impurity (II), uses relatively safe reagents and is economical to use on a commercial scale.
  • letrozole has been successfully overcome in the present invention, wherein the 1 ,2,4-triazole ring is formed during the reaction process, therefore completely eliminating the formation of any triazole regioisomers and the requirement to remove them in the purification process.
  • a first aspect of the present invention provides a process for the preparation of letrozole, or a pharmaceutically acceptable salt thereof, comprising converting 4,4'- dicyanodiphenyl methyl hydrazine, or a salt thereof, to letrozole.
  • the 4,4'-dicyanodiphenyl methyl hydrazine, or a salt thereof is converted to letrozole by reaction with 1 ,3,5-triazine.
  • the salt of the 4,4'-dicyanodiphenyl methyl hydrazine is the hydrogen chloride salt.
  • the 4,4'-dicyanodiphenyl methyl hydrazine, or a salt thereof is prepared by a process comprising the following steps:
  • step (a) is carried out under acidic conditions.
  • step (a) is carried out in a polar solvent, wherein the polar solvent is preferably an alcohol, preferably an alkyl alcohol and most preferably is methanol.
  • the ketone adduct in step (b) is a dialkyl, an arylalkyl or a diaryl ketone. Most preferably the ketone is acetone.
  • the ketone used to prepare the ketone adduct is the only solvent or the solvent is the ketone mixed with one or more additional solvents.
  • the additional solvent comprises an alcohol, more preferably an alkyl alcohol and most preferably methanol.
  • the amount of ketone in the additional solvent mixture is 30-70%, more preferably 40-60% and most preferably 50-55%.
  • step (c) is carried out using catalytic hydrogenation, wherein the catalyst is preferably palladium on charcoal.
  • step (d) is carried out using acid hydrolysis.
  • a salt of 4,4'- dicyanodiphenyl methyl hydrazine is prepared, preferably the hydrogen chloride salt.
  • the 4,4'-dicyanodiphenyl methyl hydrazine, or a salt thereof is converted to letrozole by reaction with 1,3,5-triazine in a polar solvent.
  • a polar solvent is an alcohol, preferably an alkyl alcohol, more preferably methanol, ethanol, isopropanol or a mixture thereof, and most preferably methanol.
  • the alcohol is mixed with one or more other solvents, which is/are preferably selected from cyclic ethers or halogenated alkanes or mixtures thereof.
  • the cyclic ether is tetrahydrofuran.
  • the halogenated alkane is dichloromethane.
  • the 4,4'- dicyanodiphenyl methyl hydrazine, or a salt thereof is not isolated and used in-situ.
  • a second aspect of the present invention provides a process for the preparation of 4-[l- (l,2,4-triazol-l-yl)methyl
  • the 4-cyanophenyl methyl hydrazine, or a salt thereof is converted to 4-[l-(l,2,4-triazol-l- yl)methyi]benzonitrile (III) by reaction with 1,3,5-triazine.
  • the reaction is carried out in a polar solvent, wherein the polar solvent is preferably an alcohol, preferably an alkyl alcohol.
  • the alkyl alcohol is selected from methanol, ethanol, isopropanol or a mixture thereof, most preferably methanol.
  • the 4-cyanophenyl methyl hydrazine salt is the hydrogen chloride salt.
  • the 4- cyanophenyl methyl hydrazine, or a salt thereof is prepared by a process comprising treating 4-halomethyl benzonitrile with hydrazine hydrate, wherein the halo group is chloro, bromo or iodo.
  • the halo group is bromo.
  • the 4- cyanophenyl methyl hydrazine, or a salt thereof is not isolated and used in-situ.
  • the 4-[l- (l,2,4-triazol-l-yl)methyl]benzonitrile (III) is further converted to letrozole, or a pharmaceutically acceptable salt thereof.
  • a third aspect of the present invention provides letrozole when prepared by the process according to the first or second aspect of the present invention.
  • a fourth aspect of the present invention provides letrozole substantially free of the regioisomeric impurity (II).
  • a fifth aspect of the present invention provides letrozole when prepared by the process according to the first or second aspect of the present invention, substantially free of the regioisomeric impurity (II).
  • a sixth aspect of the present invention provides letrozole with an HPLC of purity more than 99.9%, substantially free of the regioisomeric impurity (II).
  • the letrozole according to the present invention has an HPLC of purity more than 99.9%, preferably more than 99.95%, preferably more than 99.98%.
  • a seventh aspect of the present invention provides 4-[l-(l,2,4-triazol-l- yl)methyl]benzonitrile (III) when prepared by the process according to the second aspect of the present invention.
  • An eighth aspect of the present invention provides 4-[l-(l,2,4-triazol-l- yl) methyl] benzonitrile (III) substantially free of the regioisomeric impurity (V).
  • a ninth aspect of the present invention provides 4-[l-(l,2,4-triazol-l-yl)methyl]benzonitrile (III) when prepared by the process according to the second aspect of the present invention, substantially free of the regioisomeric impurity (V).
  • a tenth aspect of the present invention provides 4-[l-(l,2,4-triazol-l-yl)methyI
  • An eleventh aspect of the present invention provides a pharmaceutical composition comprising letrozole, or a pharmaceutically acceptable salt thereof, according to the third, fourth, fifth or sixth aspect of the present invention.
  • a twelfth aspect of the present invention provides the use of letrozole, or a pharmaceutically acceptable salt thereof, according to the third, fourth, fifth or sixth aspect of the present invention, or the use of a pharmaceutical composition according to the eleventh aspect of the present invention, in the manufacture of a medicament for the treatment or prevention of breast cancer.
  • a thirteenth aspect of the present invention provides a method of treating or preventing breast cancer, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of letrozole, or a pharmaceutically acceptable salt thereof, according to the third, fourth, fifth or sixth aspect of the present invention, or a therapeutically or prophylactically effective amount of a pharmaceutical composition according to the eleventh aspect of the present invention.
  • the patient is a mammal, preferably a human.
  • letrozole as used herein throughout the description and claims means letrozole and/or any salt, solvate or polymorph thereof, unless otherwise specified.
  • the letrozole or any of its intermediates such as 4-[l-(l,2,4-triazol-l-yl)methyl]benzonitrile (III) are "substantially free” of chemical or regioisomeric impurities, if they comprise less than 3% impurity, preferably less than 2%, preferably less than 1%, preferably less than 0.8%, preferably less than 0.5%, preferably less than 0.3%, preferably less than 0.2%, preferably less than 0.1% and most preferably less than 0.05%.
  • an "alkyl” group is defined as a monovalent saturated hydrocarbon, which may be straight-chained or branched, or be or include cyclic groups.
  • An alkyl group may optionally be substituted and may optionally include one or more heteroatoms N, O or S in its carbon skeleton.
  • Preferably an alkyl group is straight- chained or branched.
  • Preferably an alkyl group is not substituted.
  • an alkyl group does not include any heteroatoms in its carbon skeleton.
  • alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
  • an alkyl group is a C 1 12 alkyl group, preferably a C 1 6 alkyl group.
  • a cyclic alkyl group is a C 3 12 cyclic alkyl group, preferably a C 5 7 cyclic alkyl group.
  • aryl is defined as a monovalent aromatic hydrocarbon.
  • An aryl group may optionally be substituted and may optionally include one or more heteroatoms N, O or S in its carbon skeleton.
  • Preferably an aryl group is not substituted.
  • Preferably an aryl group does not include any heteroatoms in its carbon skeleton. Examples of aryl groups are phenyl, naphthyl, anthracenyl and phenanthrenyl groups.
  • an aryl group is a C 4 - C 14 aryl group, preferably a C 6 -C 10 aryl group.
  • letrozole can be regioselectively synthesized using hydrazines as key intermediates.
  • the letrozole thus obtained is surprisingly substantially free from the regioisomeric impurity (II) and is a major advance over the various processes described in the prior art, as discussed above.
  • the processes of the present invention comprise a unique formation of the 1 ,2,4-triazole ring from the key hydrazine intermediate in a reaction step.
  • the source of regioisomeric impurity in the prior art is the use of 1,2,4-triazole in the syntheses, as the 1,2,4-triazole will resonate while reacting and consequently the regioisomer is formed. Therefore, the processes according to the present invention construct the 1 ,2,4-tmzole ring during the synthetic sequence and formation of any unwanted regioisomer is completely eliminated.
  • the present invention provides simple, convenient and inexpensive methods for the preparation of letrozole, and its pharmaceutically acceptable salts.
  • the products obtained from the processes of the present invention are surprisingly very pure without the need for cumbersome purification techniques, such as column chromatography.
  • the present invention provides letrozole and its pharmaceutically acceptable salts substantially free of regioisomenc impurities.
  • the inventors have found that letrozole can be prepared in very high yield and purity without the regioisomenc impurity (II) by reacting the intermediate 4,4'-dicyanodiphenyl methyl hydrazine, preferably as its hydrohalide salt, with 1,3,5-tnazme.
  • Scheme 1 The reagents and solvents illustrated in Schemes 1-3 are merely illustrative of the present invention and the reaction schemes are not limited by these reagents and solvents. Any suitable alternatives can be used.
  • the first step of the preferred embodiment outlined in Scheme 1 is the preparation of 4,4'- dicyanodiphenyl hydrazone from 4,4'-dicyanobenzophenone.
  • the second step is to reduce the 4,4'-dicyanodiphenyl hydrazone to 4,4'-dicyanodiphenyl methyl hydrazine or its ketone adduct.
  • the third step is to prepare an acid salt of the 4,4'-dicyanodiphenyl methyl hydrazine by treatment with suitable organic or inorganic acids including mineral acids.
  • the hydrazine acid salt which can also be used in-situ, is then treated with 1,3,5-triazine (S- triazine) in a suitable organic medium to prepare letrozole.
  • letrozole can be further purified, if required, to obtain letrozole with more than 99.9% to 99.95% purity and completely free of any regioisomeric impurity.
  • the processes of the present invention provide a commercially viable process for the preparation of letrozole resulting in a greater than 60% molar overall yield and an HPLC purity of greater than 99.90%, preferably greater than 99.95% and more preferably greater than 99.98%.
  • Preferred embodiments according to the first aspect of the invention include a process for the preparation of letrozole, comprising the reaction of 4,4'-dicyanodiphenyl methyl hydrazine acid salt, preferably inorganic acid salts, with 1,3,5-triazine (S-triazine) in one or more polar solvents, which are preferably alkyl alcohols.
  • a preferred preparation process for the intermediate hydrazine or its salt comprises the following steps:
  • letrozole can be prepared from 4,4'-dicyanodiphenyl methyl hydrazine or its acid salt using the following steps: (i) dissolving the 4,4'-dicyanodiphenyl methyl hydrazine acid salt in a suitable polar solvent, preferably aliphatic alcohols;
  • the preparation of 4,4'-dicyanobenzophenone hydrazone is carried out in a polar solvent comprising a straight or branched aliphatic alcohol containing 1 to 5 carbon atoms.
  • a polar solvent comprising a straight or branched aliphatic alcohol containing 1 to 5 carbon atoms.
  • an acid is optionally also used, selected from an inorganic mineral acid or an organic 1 to 5 carbon chain alkanoic acid, preferably acetic acid.
  • the reduction and preparation of the ketone adduct of the 4,4'- dicyanobenzophenone hydrazone is carried out in an appropriate dialkyl ketone alone or in a mixture of dialkyl ketone and an aliphatic alcohol containing 1 to 5 carbon atoms in a straight or branched chain.
  • the ratio of dialkyl ketone in the solvent mixture is 30-70%, preferably 40-60% and most preferably 50-55%.
  • the catalytic hydrogenation is carried out using 10% palladium on charcoal catalyst, preferably in a concentration of 2-10% with respect to the weight of the substrate 4,4'-dicyanobenzophenone hydrazone.
  • the acid used in the preparation of the acid addition salt of 4,4'-dicyanodiphenyl methyl hydrazine is an organic or inorganic acid and preferably the solvent used in the preparation is a polar solvent, such as an aliphatic alcohol, preferably a 1 to 5 carbon chain straight or branched chain alcohol.
  • the acid used in the preparation of the acid addition salt of 4,4'-dicyanodiphenyl methyl hydrazine is hydrochloric acid and preferably the solvent used is either methanol, ethanol, isopropanol or a mixture thereof.
  • the reaction of 1 ,3,5-triazine with 4,4'-dicyanodiphenyl methyl hydrazine hydrochloride is carried out in a polar solvent, such as a 1 to 5 carbon atom containing straight or branched chain alcohol, alone or their mixture, preferably with one or more other solvents, preferably cyclic ethers or halogenated alkanes.
  • the polar solvents used for the reaction are preferably methanol, ethanol or isopropanol, preferably mixed with tetrahydrofuran or dichloromethane.
  • the reaction temperature is kept at between 25 to 80 0 C, preferably between 55 to 80 0 C, or more preferably 65 to 75°C.
  • letrozole is isolated from the reaction mixture by concentration of the reaction mixture, dissolving the residue in water and extraction of the aqueous layer with a water immiscible polar solvent like dichloromethane or ethyl acetate.
  • a water immiscible polar solvent like dichloromethane or ethyl acetate.
  • the letrozole is purified by a solvent mixture.
  • the letrozole is purified in a single solvent such as an alcohol or in a solvent mixture comprising an aliphatic hydrocarbon like pentane, n-hexane, n-heptane or their mixture and an aliphatic ester like ethyl, propyl, butyl or amyl acetate or propionate and mixtures thereof.
  • a second aspect of the present invention is the regioselective synthesis of intermediate 4- [l-(l,2,4-triazol-l-yl)methyl]benzonitrile (III) free from regioisomeric impurity (V) via reacting 4-cyanophenyl methyl hydrazine with 1 ,3,5-triazine (S-triazine) in a suitable organic medium (Scheme 2).
  • Preferred embodiments of the second aspect of the present invention are outlined below: (i) preparation of 4-cyanophenyl methyl hydrazine by reacting 4-bromomethyl benzonitrile with hydrazine hydrate in an alkyl alcohol, preferably methanol, and using a suitable organic/inorganic base like triethylamine or potassium carbonate; (ii) preparation of a hydrohalide salt of 4-cyanophenyl methyl hydrazine by treatment with a suitable acid solution preferably in organic medium like alcohols; and (iii) reaction of the hydrohalide salt of 4-cyanophenyl methyl hydrazine with S-triazine in an appropriate organic medium at a temperature of about 50 to 75°C.
  • letrozole is prepared from intermediate (III), prepared according to the second aspect of the present invention, by its reaction with 4-fluorobenzonitrile (IV) in the presence of strong base like potassium tert-butoxide as described in patent US 4,978,672 and other prior art processes described above (see also Scheme 3).
  • the letrozole is prepared with an HPLC purity of more than 99.95%, substantially free of the regioisomeric impurity (II).
  • the products are obtained in a yield of 70% or more, preferably 80% or more, preferably 90% or more, preferably 95% or more.
  • the letrozole is obtained substantially free of chemical impurities.
  • the letrozole is obtained on a commercial scale, preferably in batches of lkg or more, 10kg or more, 100kg or more, 500kg or more, or 1000kg or more.
  • the pharmaceutical composition according to the eleventh aspect of the present invention can be a solution or suspension form, but is preferably a solid oral dosage form.
  • Preferred dosage forms in accordance with the invention include tablets, capsules and the like which, optionally, may be coated if desired. Tablets can be prepared by conventional techniques, including direct compression, wet granulation and dry granulation. Capsules are generally formed from a gelatine material and can include a conventionally prepared granulate of excipients in accordance with the invention.
  • the pharmaceutical composition according to the present invention typically comprises one or more conventional pharmaceutically acceptable excipient(s) selected from the group comprising a filler, a binder, a disintegrant, a lubricant and optionally further comprises at least one excipient selected from colouring agents, adsorbents, surfactants, film-formers and plasticizers.
  • the pharmaceutical composition of the invention typically comprises one or more fillers, such as microcrystalline cellulose, lactose, sugars, starches, modified starches, mannitol, sorbitol and other polyols, dextrin, dextran or maltodextrin; one or more binders, such as lactose, starches, modified starch, maize starch, dextrin, dextran, maltodextrin, microcrystalline cellulose, sugars, polyethylene glycols, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, gelatin, acacia gum, tragacanth, polyvinylpyrrolidone or crospovidone; one or more disintegrating agents, such as croscarmellose sodium, cross- linked polyvinylpyrrolidone, crospovidone, cross-linked carboxymethyl starch, starches,
  • the coating may be prepared from at least one film-former such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose or methacrylate polymers which optionally may contain at least one plasticizer such as polyethylene glycols, dibutyl sebacate, triethyl citrate, and other pharmaceutical auxiliary substances conventional for film coatings, such as pigments, fillers and others.
  • the twelfth aspect of the present invention provides the use of a pharmaceutical composition according to the eleventh aspect of the present invention in the manufacture of a medicament for the treatment of cancer, in particular for the treatment of breast cancer in postmenopausal women.
  • Example 2 2-(propan-2-yUdine)-l-[di-(4-cyanophenyl)methyl]hydrazine (VIII)
  • a solution of 100 g (0.406 mol) of 4,4'-dicyanobenzophenone hydrazone (VII) was added to 3600 ml equal volume mixture of methanol and acetone at 25-30 0 C.
  • 7.5 g of palladium 10% on carbon was suspended under an inert (preferably nitrogen) atmosphere.
  • hydrogen gas was bubbled at atmospheric pressure.
  • Example 3 4-[l-(4-cyanophenyl)-l-(1.2.4-tria2ol-l-yl)methyl]ben2onitrile (letrozole) In a suitable glass reaction vessel, a solution of 100 g (0.35 mol) of 2-(propan-2-ylidine)-l-
  • hydrazine hydrate (40.8 g, 1.02 mol) and triethylamine (26 g, 0.248 mol) were added to methanol (125 ml).
  • methanol 125 ml
  • 4- bromomethyl benzonitrile 25 g, 0.128 mol
  • methanol 375 ml
  • the reaction mixture was stirred at the same temperature for 5 to 7 hours.
  • the solvent was removed by distillation at 40-50 0 C under reduced pressure.
  • water (200 ml) and dichloromethane 100 ml were added and the mixture stirred for 15 minutes.
  • the 4-cyanophenyl methyl hydrazine (20 g, 0.14 mol) was dissolved in methanol (100 ml) and treated with a 35% aqueous solution of hydrochloric acid (12 ml) at 10-15 0 C under stirring to obtain 4-cyanophenyl methyl hydrazine hydrochloride.
  • 1,3,5- triazine (S-triazine) (66 g, 0.81 mol) dissolved in methanol (330 ml) was slowly added.
  • the reaction mixture temperature was slowly increased to reflux and the reaction mixture refluxed for 5 to 6 hours. After completion of the reaction, the reaction mixture was concentrated by distillation of the solvent. To the residue, water was added and the reaction mixture was extracted with dichloromethane.
  • HPLC purity >99.5% (Regioisomer impurity (V) could not be detected.)
  • the 4-[l-(l,2,4-triazol-l-yl)methyl]benzonitrile (III) prepared in accordance with example 4 was converted into letrozole using 4-fluorobenzonitrile (IV) in the presence of strong base such as potassium tert-butoxide as described in the prior art, for example, in patent US 4,978,672.
  • the HPLC purity of the letrozole obtained was >99.9%; the regioisomer impurity (II) could not be detected.

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  • Organic Chemistry (AREA)
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Abstract

L'invention concerne un procédé amélioré de préparation de létrozole (I) et de sels pharmaceutiquement acceptables de ce composé, des compositions comprenant du létrozole ou un sel pharmaceutiquement acceptable de ce composé, et des applications de telles compositions. L'invention concerne en particulier un procédé et de nouveaux produits intermédiaires utiles dans la préparation de létrozole et de sels de ce composé, qui sont sensiblement exempts d'impuretés régio-isomères.
PCT/GB2010/050993 2009-06-15 2010-06-14 Synthèse régiosélective de létrozole WO2010146391A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012025762A3 (fr) * 2010-08-27 2012-05-03 Generics [Uk] Limited Intermédiaire pur
WO2013040337A1 (fr) * 2011-09-14 2013-03-21 Exelixis, Inc. Inhibiteurs de phosphatidylinositol 3-kinase pour le traitement du cancer

Citations (6)

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Publication number Priority date Publication date Assignee Title
US4978672A (en) 1986-03-07 1990-12-18 Ciba-Geigy Corporation Alpha-heterocyclc substituted tolunitriles
WO2003050093A1 (fr) * 2001-12-11 2003-06-19 Emory University Bis(cyanophenyl)methyl-triazole a utiliser pour la prevention du cancer du sein
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
WO2005047269A1 (fr) 2003-11-14 2005-05-26 Natco Pharma Limited Procede de separation du precurseur de 4- 1-(1,2,4-triazolyl) methyl!benzonitrile et de son isomere 1,3,4-triazolyle
WO2007039912A1 (fr) 2005-10-05 2007-04-12 Usv Limited Procede monotope permettant de preparer un 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile
WO2007144896A1 (fr) 2006-06-13 2007-12-21 Natco Pharma Limited Procédé de préparation de létrozole

Patent Citations (6)

* 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
WO2003050093A1 (fr) * 2001-12-11 2003-06-19 Emory University Bis(cyanophenyl)methyl-triazole a utiliser pour la prevention du cancer du sein
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
WO2005047269A1 (fr) 2003-11-14 2005-05-26 Natco Pharma Limited Procede de separation du precurseur de 4- 1-(1,2,4-triazolyl) methyl!benzonitrile et de son isomere 1,3,4-triazolyle
WO2007039912A1 (fr) 2005-10-05 2007-04-12 Usv Limited Procede monotope permettant de preparer un 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile
WO2007144896A1 (fr) 2006-06-13 2007-12-21 Natco Pharma Limited Procédé de préparation de létrozole

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2013040337A1 (fr) * 2011-09-14 2013-03-21 Exelixis, Inc. Inhibiteurs de phosphatidylinositol 3-kinase pour le traitement du cancer

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