cas 112809-51-5, Letrozole | Articles data

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A novel process for the synthesis of substantially pure Letrozole
This article demonstrates an improved novel and practical synthesis of oral non-steroidal aromatase inhibitor (AI) Letrozole in a five-stage synthetic process in excellent yields. Key steps of the synthesis involve the condensation of 4-(chloro(4-cyanophenyl)methyl)benzamide with 1H-1,2,4-triazole and further its dehydration to Letrozole by using trifluoroacetic anhydride at low temperature.
Suman,Vijayabhaskar,NageswaraRao,Syam Kumar,VenkateswaraRao
p. 1 - 8
(2019)
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Preparation method of letrozole
To the method, a continuous flow chemical technology is adopted to prepare the key intermediate, and the temperature of the reaction is accurately controlled. The content of triazole isomeric impurities 4 - [α - (4 - cyanophenyl) -1 - (1, 3, 4 - triazolyl) methyl] - benzonitrile is reduced, so that repeated recrystallization is avoided, the yield is improved, the total yield is 44% more than 67%, and the cost is saved.
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Paragraph 0032; 0034-0035; 0037-0038; 0040-0041; 0043

(2021/11/10)

Nickel-Catalyzed Cyanation of Aryl Thioethers
A nickel-catalyzed cyanation of aryl thioethers using Zn(CN)2 as a cyanide source has been developed to access functionalized aryl nitriles. The ligand dcype (1,2-bis(dicyclohexylphosphino)ethane) in combination with the base KOAc (potassium acetate) is essential for achieving this transformation efficiently. This reaction involves both a C-S bond activation and a C-C bond formation. The scalability, low catalyst and reagents loadings, and high functional group tolerance have enabled both late-stage derivatization and polymer recycling, demonstrating the reaction's utility across organic chemistry.
Delcaillau, Tristan,Woenckhaus-Alvarez, Adrian,Morandi, Bill
supporting information
p. 7018 - 7022
(2021/09/13)

Nickel-Catalyzed Reversible Functional Group Metathesis between Aryl Nitriles and Aryl Thioethers
We describe a new functional group metathesis between aryl nitriles and aryl thioethers. The catalytic system nickel/dcype is essential to achieve this fully reversible transformation in good to excellent yields. Furthermore, the cyanide- and thiol-free reaction shows high functional group tolerance and great efficiency for the late-stage derivatization of commercial molecules. Finally, synthetic applications demonstrate its versatility and utility in multistep synthesis.
Delcaillau, Tristan,Boehm, Philip,Morandi, Bill
supporting information
p. 3723 - 3728
(2021/04/07)

Immobilized palladium nanoparticles on a cyclodextrin-polyurethane nanosponge (Pd-CD-PU-NS): An efficient catalyst for cyanation reaction in aqueous media
Immobilized palladium nanoparticles on a cyclodextrin-polyurethane nanosponge (Pd-CD-PU-NS) were found to be an efficient heterogeneous catalyst in the cyanation reaction of aryl halides in aqueous media. This catalyst system is containing palladium nanoparticles with a size of ～7 nm. Moreover, the CD-PU-NS support formed microsphere-shaped structures with a size of ～100–200 nm. The TEM images show that Pd nanoparticles were formed in near spherical shape morphology and were immobilized in the structure of the CD-PU-NS support. Under our optimized reaction conditions, aryl cyanides were obtained in high yields in the presence of the Pd-CD-PU-NS catalyst. Our results demonstrated that the Pd-CD-PU-NS catalyst is highly effective in the cyanation reaction in aqueous media. Furthermore, the catalyst could be simply extracted from the reaction mixture, providing an efficient methodology for the synthesis of aryl cyanides. The Pd-CD-PU-NS catalyst could be recycled four times with almost consistent catalytic efficiency.
Khajeh Dangolani, Soheila,Sharifat, Sara,Panahi, Farhad,Khalafi-Nezhad, Ali
supporting information
p. 256 - 265
(2019/06/07)

Preparation method of aromatic nitrile compound or heteroaromatic nitrile compound
The invention discloses a preparation method of an aromatic nitrile compound or a heteroaromatic nitrile compound. The preparation method comprises: under the protection of an inert gas, in a solvent,under the actions of a nickel catalyst, a ligand, metal zinc and an additive, carrying out a reaction on a cyanation reagent and halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon. According to the present invention, by using the inexpensive and easily-available nickel catalyst and the ligand, the halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon,especially the chlorinated aromatic hydrocarbon or chlorinated heteroaromatic hydrocarbon with characteristics of low price, easy obtaining and low reaction activity can mildly and efficiently react with the cyanation reagent with low toxicity to prepare the aromatic nitrile compound or heteroaromatic nitrile compound; and the preparation method has advantages of simple operation, mildness, high efficiency and the like, and further has characteristics of good functional group compatibility, good universality of substrate and the like.
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Paragraph 0231-0233

(2018/11/03)

General and Mild Nickel-Catalyzed Cyanation of Aryl/Heteroaryl Chlorides with Zn(CN)2: Key Roles of DMAP
A new and general nickel-catalyzed cyanation of hetero(aryl) chlorides using less toxic Zn(CN)2 as the cyanide source has been developed. The reaction relies on the use of inexpensive NiCl2·6H2O/dppf/Zn as the catalytic system and DMAP as the additive, allowing the cyanation to occur under mild reaction conditions (50-80 °C) with wide functional group tolerance. DMAP was found to be crucial for successful transformation, and the reaction likely proceeds via a Ni(0)/Ni(II) catalysis based on mechanistic studies. The method was also successfully extended to aryl bromides and aryl iodides.
Zhang, Xingjie,Xia, Aiyou,Chen, Haoyi,Liu, Yuanhong
supporting information
p. 2118 - 2121
(2017/04/27)

Ex situ generation of stoichiometric HCN and its application in the Pd-catalysed cyanation of aryl bromides: Evidence for a transmetallation step between two oxidative addition Pd-complexes
A protocol for the Pd-catalysed cyanation of aryl bromides using near stoichiometric and gaseous hydrogen cyanide is reported for the first time. A two-chamber reactor was adopted for the safe liberation of ex situ generated HCN in a closed environment, which proved highly efficient in the Ni-catalysed hydrocyanation as the test reaction. Subsequently, this setup was exploited for converting a range of aryl and heteroaryl bromides (28 examples) directly into the corresponding benzonitriles in high yields, without the need for cyanide salts. Cyanation was achieved employing the Pd(0) precatalyst, P(tBu)3-Pd-G3 and a weak base, potassium acetate, in a dioxane-water solvent mixture. The methodology was also suitable for the synthesis of 13C-labelled benzonitriles with ex situ generated 13C-hydrogen cyanide. Stoichiometric studies with the metal complexes were undertaken to delineate the mechanism for this catalytic transformation. Treatment of Pd(P(tBu)3)2 with H13CN in THF provided two Pd-hydride complexes, (P(tBu)3)2Pd(H)(13CN), and [(P(tBu)3)Pd(H)]2Pd(13CN)4, both of which were isolated and characterised by NMR spectroscopy and X-ray crystal structure analysis. When the same reaction was performed in a THF : water mixture in the presence of KOAc, only (P(tBu)3)2Pd(H)(13CN) was formed. Subjection of this cyano hydride metal complex with the oxidative addition complex (P(tBu)3)Pd(Ph)(Br) in a 1 : 1 ratio in THF led to a transmetallation step with the formation of (P(tBu)3)2Pd(H)(Br) and 13C-benzonitrile from a reductive elimination step. These experiments suggest the possibility of a catalytic cycle involving initially the formation of two Pd(ii)-species from the oxidative addition of LnPd(0) into HCN and an aryl bromide followed by a transmetallation step to LnPd(Ar)(CN) and LnPd(H)(Br), which both reductively eliminate, the latter in the presence of KOAc, to generate the benzonitrile and LnPd(0).
Kristensen, Steffan K.,Eikeland, Espen Z.,Taarning, Esben,Lindhardt, Anders T.,Skrydstrup, Troels
p. 8094 - 8105
(2017/11/27)

Preparation method of letrozole
The invention provides a preparation method of letrozole (6). The preparation method comprises the following steps: reacting a compound (1) with a compound (3) under the effect of an alkaline matter; performing a bromination reaction of the compound (3) to obtain a compound (4); condensing the compound (4) and 4-amino-1,2,4-triazole (5); and performing diazotization to remove the amino to obtain letrozole (6). According to the method provided by the invention, the route is simple; the cheap and easily available p-chlorobenzonitrile and p-tolunitrile are adopted as starting raw materials, and the target product letrozole is obtained through 3 steps of reactions in total; and the preparation method has the advantages of mild reaction conditions, simple and convenient operation, high yield, good chemical selectivity and low production cost, is suitable for industrial production and brings relatively great practical application value and social economic benefits.
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Paragraph 0064; 0065

(2017/04/07)

Letrozole a process for synthesizing
The invention discloses a process for synthesizing letrozole. The process is characterized by reacting compounds in a structural formula I, a structural formula II and a structural formula III in an environment with a catalyst system, an organic solvent and a certain reaction temperature, thus preparing letrozole. In the process for preparing letrozole, an intermediate is unnecessary to be separated, thus really achieving one-pot reaction; in the reaction, as letrozole molecules are prepared by adopting a series mode, other needed substituent groups can be retained, and other needed functional groups can be introduced, thus preparing various needed function model drug molecules.
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Paragraph 0016; 0017

(2017/03/08)

One-pot transformation of methylarenes into aromatic nitriles with inorganic metal-free reagents
Various methylarenes were transformed into the corresponding aromatic nitriles in good to moderate yields by the treatment with aq. HBr and aq. H 2O2, followed by reaction with molecular iodine and aq. ammonia in a one-pot procedure. The present reaction is a useful, practical, transition-metal-free, and organic-reagent-free method for the preparation of aromatic nitriles from methylarenes. Various methylarenes were treated with aq. HBr and aq. H2O2 under warming conditions and/or irradiation conditions, followed by the reaction with molecular iodine and aq. ammonia, to provide the corresponding aromatic nitriles, in a one-pot procedure. The present reaction was carried out under metal-free and organic-reagent-free conditions. Copyright
Kawagoe, Yuhsuke,Moriyama, Katsuhiko,Togo, Hideo
p. 4115 - 4122
(2014/07/08)

A base-induced ring-opening process of 2-substituted-1,3,4-oxadiazoles for the generation of nitriles at room temperature
A novel base-catalysed 1,3,4-oxadiazole fragmentation for the synthesis of nitriles at room temperature has been developed. This reaction is performed under transition-metal-free conditions, and provides a new ring cleavage reaction of 1,3,4-oxadiazoles in organic synthesis.
Lu, Guo-Ping,Lin, Ya-Mei
p. 371 - 374
(2014/07/08)

USE OF AN AROMATASE INHIBITOR FOR THE TREATMENT OF HYPOGONADISM AND RELATED DISEASES
This invention relates to a method of increasing testosterone levels and treating hypogonadism and related diseases with the aromatase inhibitor 4,4'-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile. The present invention further relates to a method of increasing testosterone levels and treating hypogonadism and related diseases with the aromatase inhibitor 4,4'-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile in a particular dosing regimen. The invention also relates to pharmaceutical compositions comprising said aromatase inhibitor 4,4'-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, optionally in combination with other active ingredients. Furthermore, the present invention relates to kits comprising said pharmaceutical compositions together with instructions how to administer them.
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Paragraph 134; 135

(2013/03/26)

New ruthenium(II)-letrozole complexes as anticancer therapeutics
Novel ruthenium-letrozole complexes have been prepared, and cell viability of two human cancer cell types (breast and glioblastoma) was determined. Some ruthenium compounds are known for their cytotoxicity to cancer cells, whereas letrozole is an aromatas
Castonguay, Annie,Doucet, Cédric,Juhas, Michal,Maysinger, Dusica
p. 8799 - 8806
(2013/01/15)

Aluminum triflate as a powerful catalyst for direct amination of alcohols, including electron-withdrawing group-substituted benzhydrols
Direct aminations of allylic alcohols, benzylic alcohols, and benzhydrols with electron-withdrawing (F, Br, I, NO2, or CN) substituents were efficiently catalyzed by aluminum triflate [Al(OTf)3] to afford the corresponding biarylamines in high yield, and the dibromo-substituted product was further transformed into letrozole. Copyright
Ohshima, Takashi,Ipposhi, Junji,Nakahara, Yasuhito,Shibuya, Ryozo,Mashima, Kazushi
supporting information
p. 2447 - 2452
(2012/11/07)

PURE INTERMEDIATE
The present invention relates to an improved process for the preparation of Letrozole (I) and its synthetic intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III). In particular, it relates to a process to prepare Letrozole and its intermediate (III) substantially free from regioisomeric impurities. The present invention further relates to acid addition salts of 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) such as the oxalate salt, and also to Letrozole (I), the intermediate (III) and salts thereof preparable by the processes of the present invention.
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(2012/03/26)

PROCESS FOR PREPARATION OF LETROZOLE AND ITS INTERMEDIATES
The present invention relates to an improved process for preparation of the non-steroidal aromatase inhibitor drug, Letrozole of formula (I) and its intermediates, 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile of formula (IV) and 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile hydrochloride of formula (VII), all having a purity of ≧99%, which is simple, convenient, economical, does not use hazardous chemicals and industrially viable.
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Page/Page column 19

(2010/09/18)

REGIOSELECTIVE SYNTHESIS OF LETROZOLE
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. In particular it relates to a process and to novel intermediates for preparing letrozole and its salts substantially free from regioisomeric impurities.
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Page/Page column 18-19

(2010/12/31)

Process for the Preparation of Letrozole
The present invention relates to the process for the preparation of Letrozole free from its regioisomer (7) and other impurities by selective extraction of desired intermediate (3) using suitable solvent and mixture of solvents.
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Page/Page column 6

(2010/08/07)

AN IMPROVED PROCESS FOR PREPARATION OF LETROZOLE AND ITS INTERMEDIATES
The present invention relates to an improved process for preparation of the non-steroidal aromatase inhibitor drug, Letrozole of formula (I) and its intermediates, 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile of formula (IV) and 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile hydrochloride of formula (VII), all having a purity of ≥99%, which is simple, convenient, economical, does not use hazardous chemicals and industrially viable.
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Page/Page column 42-43

(2009/07/03)

PROCESS AND INTERMEDIATE OF LETROZOLE
The present invention relates to a process for the preparation of Letrozole involving the use of novel intermediate of Formula I.
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Page/Page column 5; 6

(2009/07/18)

NOVEL THERMODYNAMICALLY STABLE POLYMORPHIC FORM-L OF LETROZOLE
The present invention relates to a novel crystalline Form L of letrozole and a process for preparing the same. Letrozole is useful for the first-line treatment in post-menopausal women with hormone receptor positive (or) locally advanced (or) metastatic breast cancer.
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Page/Page column 5

(2008/12/07)

Letrozole production process
Provided is a method for preparing letrozole, which includes reacting an activated bis-(4-cyanophenyl)-methane with a triazole to produce letrozole, and, optionally, purifying the letrozole. Also provided are highly pure letrozole, and a method of purifying letrozole, which method includes precipitating letrozole, e.g., by selective precipitation from a reaction mixture and/or by subjecting the letrozole to one or more crystallizations.
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Page/Page column 7

(2008/06/13)

PROCESS FOR THE PREPARATION OF LETROZOLE
The present invention relates to the process for the preparation of Letrozole free from its regioisomer (7) and other impurities by selective extraction of desired intermediate (3) using suitable solvent and mixture of solvents.
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Page/Page column 5; 11-12

(2008/06/13)

A METHOD OF MANUFACTURE OF LETROZOLE
A novel and convenient method of manufacture of letrozole of formula (I) is described. Letrozole is an aromatase inhibitor drug used in the treatment of postmenopausal breast cancer.
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Page/Page column 7; 9

(2008/06/13)

SYNTHESIS OF 4-[1-(4-CYANO PHENYL)-(1,2,4-TR1AZOL-1-YL)METHYL] BENZONITRILE AND 4-[1-(1H-1,2,4-TRIAZOL-1-YL)METHYLENE BENZONITRILE INTERMEDIATE
The present invention relates to a process for the preparation of 4-[1-(4-cyano phenyl)-1- (1 ,2,4-triazol-1-yl) methyl] benzonitrile (letrozole), substantially free from its isomeric impurity. The preparation involves reaction of 4-[1-(1 H-1 ,2,4-triazol-1-yl)methylene benzonitrile with 4-fluorobenzonitrile in the presence of an organic solvent and a silicon amine. The present invention also relates to a process for the preparation of 4-[1-(1 H- 1 ,2,4-triazol-1-yl)methylene benzonitrile which involves: (a) the reaction of a 4-halomethyl benzonitrile with 1 ,2,4-triazole in the presence of cesium carbonate and an organic solvent to obtain a reaction mass comprising 4-[1-(1 ,2,4-triazole-1-yl)methyl] benzonitrile of formula II; and (b) precipitation of 4-[1-(1 ,2,4-triazole-1-yl)methyl]benzonitrile (II) from the reaction mass using a suitable organic solvent.
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Page/Page column 13; 15; 17

(2008/06/13)

CRYSTALLINE FORMS OF LETROZOLE AND PROCESSES FOR MAKING THEM
Crystalline forms of letrozole can be made by precipitation and are useful in making pharmaceutical compositions.
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Page/Page column 4

(2008/06/13)

Process for the preparation of letrozole
The invention provides a high-yield process for the preparation of letrozole having a high purity, without the need for removal of the 4-[1-(1,3,4-triazolyl)methyl]benzonitrile impurity at the intermediate stage. The invention also provides a process for the synthesis of letrozole in which formation of the impurity 4-[1-(1,3,4-triazolyl)methyl]benzonitrile during the first stage is minimized. In the process, a 4-(halomethyl)benzonitrile is reacted with a salt of 1H-1,2,4-triazole, reducing the formation of the impurity. Preferably, the preparation is conducted as a one-pot process.
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Page/Page column 9

(2010/11/26)

A ONE POT PROCESS FOR THE PREPARATION OF 4-[1-CYANOPHENYL)-1-(1,2,4-TRIAZOL-1-YL)METHYL]BENZONITRILE
The invention discloses a one pot process for the preparation of highly pure 4-[l-cyanophenyl)-l- (1,2,4-triazol-l-yl) methyl] benzonitrile (Letrozole) without isolation of the intermediate 4-[l- (l,2,4-triazol-l-yl)methyl]benzonitrile. oc-Bromotolunitrile is condensed with alkali metal salt of 1 ,2,4-triazole in an organic solvent. 4-Fluorobenzonitrile is charged into the condensate in the presence of a base to give crude Letrozole which is purified by recrystallization alone or in combination with column chromatography.
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Page/Page column 10-11

(2010/11/26)

PROCESS FOR PREPARING LETROZOLE
A process for preparing letrozole, and purified letrozole.
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Page/Page column 7

(2010/11/27)

NOVEL INTERMEDIATES FOR PREPARATION OF LETROZOLE
The invention provides novel intermediates of formula (II), wherein R1 and R2 are same and are selected from methyl, CH (OCOCH3) 2, CHO or CH=N-OH, a process for preparation thereof and a process for preparation of Letrozole of formula (I), utilizing the said novel intermediates of formula (II).
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Page/Page column 14; 19

(2010/11/27)

PROCESS FOR PREPARING LETROZOLE
A process for preparing letrozole by reacting p-fluorobenzonitrile with 4[1-(1,2,4- triazolyl)methyl]benzonitrile in the presence of an alkali metal alkoxide, characterised in that it comprises adding : 5 A) simultaneously separate solutions of respectively p-fluorobenzonitrile and 4[1- (1,2,4-triazolyl)methyl]benzonitrile in an aprotic dipolar solvent, or alternatively B) a unique solution of a mixture of p-fluorobenzonitrile and 4[1-(1,2,4- triazolyl)methyl]benzonitrile in an aprotic dipolar solvent, to a solution of said alkali metal alkoxide in the same dipolar aprotic solvent of (A) 10 or (B).
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Page/Page column 7-8

(2010/11/28)

REGIOSPECIFIC PROCESS FOR THE PREPARATION OF 4-[1- (4-CYANOPHENYL)-1-(1,2,4-TRIAZOL-1-YL)METHYL]BENZONITRILE
A regiospecific process for the preparation of 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile comprising reacting 4-halomethylbenzonitrile with 4-amino-1,2,4-triazole followed by deamination and reaction with 4-fluorobenzonitrile.
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Page/Page column 10

(2008/06/13)

ALPHA-HETEROCYCLC SUBSTITUTED TOLUNITRILES
The invention is concerned with aromatase inhibiting compounds of formula I wherein R and Ro represent hydrogen or lower alkyl; or R and Ro located on adjacent carbon atoms and together when combined with the benzene ring to which they are attached form a naphthalene or tetrahydronaphthalene ring; R1 and R2 independently represent hydrogen, lower alkyl, (lower alkyl, aryl or aryl-lower alkyl)-thio, lower alkenyl, aryl, aryl-lower alkyl, C3-C6-cycloalkyl, or C3-C6-cycloalkyl-lower alkyl; or R1 and R2 combined represent lower alkylidene, mono or di-aryl-lower alkylidene; R1 and R2 combined also represent C4-C6-straight chain alkylene, lower alkyl-substituted straight chain alkylene or ortho-phenylene bridged-C2-C4 -straight chain alkylene, each forming with the carbon atom attached thereto a corresponding optionally substituted or benzo-fused 5, 6 or 7-membered ring; W represents 1-imidazolyl, 1-(1,2,4- or 1,3,4)-triazolyl or 3-pyridyl; or W represents 1-imidazolyl, 1-(1,2,4 or 1,3,4)-triazolyl or 3-pyridyl substituted by lower alkyl; and pharmaceutically acceptable salts thereof
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(2008/06/13)