- Preparation method of anastrozole intermediate 3, 5 -bis (2 -cyanopropyl -2 -yl) bromotoluene
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The invention relates to a preparation method of anastrozole key intermediate 3, 5 - bis (2 -cyanopropyl -2 - radical) bromotoluene, adopts a continuous flow chemical technology to prepare 3, 5 - bis (2 -cyanopropyl -2 - radical) bromotoluene, and controls the reaction temperature accurately. The feeding amount, the feeding rate and the reaction time can be controlled accurately, so that the yield is high (_AOMARKENCODEGTX0AOA). 95%) With good purity (_AOMARKENCODEGTX0AOA) 94%-(3)-5 -(2 -cyanopentanoic -2 -yl) bromotoluene.
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Paragraph 0010; 0020-0027
(2021/11/10)
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- A process for synthesizing preparing anastrozole
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The invention discloses a method for preparing anastrozole. The anastrozole is prepared by using a,a,a',a',5-pentamethyl-1,3-diacetonitrile benzene as a starting material, bromizing under the action of a brominating agent NBS to generate a midbody 3,5-bi[(2,2-dimethyl)cyan methyl]-benzyl bromide, and catalyzing and condensing the midbody with 1,2,4-triazole in water and organic solvent by phase transfer to prepare anastrozole. The method has the advantages of simplicity in operation, mild reaction condition, high yield and high purity of products, and is suitable for industrial production of anastrozole.
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Paragraph 0014-0016
(2017/01/23)
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- METHOD FOR PREPARING ANASTROZOLE FOR PHARMACEUTICAL PURPOSES
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A method for preparing anastrozole characterised in that it comprises; - a bromination step, wherein 2-2' (5-methyl-1, 3- phenylene) bis (2-methylpropanenitrile) is subject to a bromination reaction in the presence of an ester solvent so as to obtain 2- [3 -bromomethyl-5 - (cyano-dimethyl-methyl) -phenyl] - 2-methyl-propanenitrile; - a nucleophilic substitution step, wherein an organic mixture comprising unreacted 2-2' ( 5-methyl-l, 3 -phenylene) bis (2- methylpropanenitrile), the 2- [3 -bromomethyl-5- (cyano-dimethyl- methyl) -phenyl] -2 -methyl-propanenitrile formed and, if necessary, other reaction by-products is caused to react in dimethylformamide with 1-2-4-triazole or with its sodium salt at a temperature ranging from 0 to 25 °C for the formation of anastrozole; - an anastrozole purification step.
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Page/Page column 4
(2014/12/12)
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- How to use the Lasentec FBRM probe on manufacturing scale
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A Lasentec FBRM probe was installed in a 450-L production unit and deployed to monitor the final three stages of the manufacturing process. Each step features a different type of crystallization: reactive, pH switch and cooling. In total over 100 batches were monitored. The probe detected 'oiling out' and seeding with agitation but did not detect 'bearding' or seeding without agitation. There was remarkable consistency from batch to batch, except for the first batches in some campaigns, which more closely resembled laboratory experiments. The challenge of interpreting Lasentec FBRM data in a production environment is addressed and compared with the alternative, in process control (IPC).
- Adlington, Neil K.,Black, Simon N,Adshead, David L
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p. 557 - 567
(2013/05/09)
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- A process for the preparation of a benzylbromide intermediates
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The present invention relates to the improved process for the preparation of 3,5-bis-(1-cyano-1-methylethyl)benzylbromide free from impurities such as 2,2-(5-methyl-1,3-phenylene)-bis(2-methylpropionitrile) and 3,5-bis(1-cyano-1-methylethyl)-α,α-diibromotoluene.
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Page/Page column 5
(2012/01/06)
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- Process for the Preparation of Pure Anastrozole
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A process for the preparation of anastrozole which comprises: a) brominating 3,5-bis(2-cyanoprop-2-yl)toluene (II) in an organic solvent using a brominating agent to obtain 3,5-bis(2-cyanoprop-2-yl)benzylbromide (III); b) heating the reaction mass of step a) to the reflux temperature of the organic solvent for a period of time no longer than 3 hours; c) isolating and purifying the bromo intermediate (III) using an organic solvent; d) alkylating the bromo intermediate in the presence of a base, optionally a phase transfer catalyst, a 1,2,4-triazole and an organic solvent to obtain anastrozole; and e) isolating and purifying the anastrozole from an organic solvent.
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Page/Page column 6
(2010/05/13)
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- Process for the Preparation of Pure Anastrozole
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The present invention relates to the improved process for the preparation of Anastrozole free from the impurities arising due to impure 3,5-bis-(1-cyano-1-methylethyl)benzylbromide (2) and other related impurities resulting from incomplete/over-reaction of 2,2-(5-methyl-1,3-phenylene)-bis(2-methylpropionitrile (I).
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Page/Page column 4
(2009/09/08)
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- PROCESS FOR THE PREPARATION OF PURE ANASTROZOLE
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A process for the preparation of anastrozole which comprises: a) brominating 3,5-bis(2-cyanoprop-2-yl)toluene (II) in an organic solvent using a brominating agent to obtain 3,5- bis(2-cyanoprop-2-yl)benzylbromide (III); b) heating the reaction mass of step a) to the reflux temperature of the organic solvent for a period of time no longer than 3 hours; c) isolating and purifying the bromo intermediate (III) using an organic solvent; d) alkylating the bromo intermediate in the presence of a base, optionally a phase transfer catalyst, a 1,2,4-triazole and an organic solvent to obtain anastrozole; and e) isolating and purifying the anastrozole from an organic solvent.
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Page/Page column 16; 17
(2008/12/05)
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- Process for the Preparation of 2,2'-[5-(1H-1,2,4-Triazole-1-Ylmethyl) -1,3-Phenylene] Di (2-Methylpropionitrile)
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The present invention discloses a process for the preparation of Anastrozole of the formula I in high purity and in high yield. 3,5-bis(halomethyl)toluene is prepared by reacting mesitylene with N-halosuccinimide in the presence of light or dibenzoyl peroxide or azobis isobutyronitrile as a catalyst and in a chlorinated solvent. 3,5-bis(halomethyl)toluene is cyanated with metal cyanide in the presence of a catalyst and in water, organic solvent or mixture thereof at temperature of 40 to 60° C. to obtain 2,2′-(5-methyl-1,3 phenylene)diacetonitrile which is further methylated with iodomethane in the presence of base and an organic solvent at temperature of 0 to 15° C. to obtain 2,2′-(5-methyl-1,3-phenylene)di(2-methyl-propiononitrile). The product obtained is treated with N-halosuccinimide in the presence of a catalyst and in a chlorinated solvent at temperature of 60 to 100° C. to obtain 2,2′-(5-halomethyl-1,3-phenylene)di(2-methyl propionitrile) which was further treated with potassium or sodium salt 1,2,4-triazole at temperature of 20 to 50° C. in dimethyl formamide to obtain crude 2,2′-[5-(1H-1,2,4-triazole-1-ylmethyl)-1,3-phenylene]di(2-methyl-propionitrile). The crude product is purified by column chromatography using a stationary phase and a mobile phase followed by recrystallization with a solvent or mixture of solvents to obtain highly pure Anastrozole.
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Page/Page column 5
(2008/12/08)
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- PROCESS FOR THE PREPARATION OF 2,2’-[5-(1,2,4-TRIAZOLE-1-YLMETHYL) -1,3-PHENYLENE] DI (2-METHYLPROPIONITRILE).
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The present invention discloses a process for the preparation of Anastrozole of the formula I in high purity and in high yield. 3,5-bis(halomethyl)toluene is prepared by reacting mesitylene with N-halosuccinimide in the presence of light or dibenzoyl peroxide or azobis isobutyronitrile as a catalyst and in a chlorinated solvent. 3,5-bis(halomethyl)toluene is cyanated with metal cyanide in the presence of a catalyst and in water, organic solvent or mixture thereof at temperature of 40 to 60° C to obtain 2,2'-(5-methyl-l,3 phenylene)diacetonitrile which is further methylated with iodomethane in the presence of base and an organic solvent at temperature of 0 to 15° C to obtain 2,2'-(5-methyl-l,3-phenylene)di(2-methyl-propiononitrile). The product obtained is treated with N-halosuccinimide in the presence of a catalyst and in a chorinated solvent at temperature of 60 to 100° C to obtain 2,2'-(5-halomethyl-l,3-phenylene)di(2-methyl propionitrile) which was further treated with potassium or sodium salt 1,2,4-triazole at temperature of 20 to 50° C in dimethyl formamide to obtain crude 2,2'-[5-(lH-l,2,4-triazole-l-ylmethyl)-l,3-phenylene]di(2- methylpropionitrile). The crude product is purified by column chromatography using a stationary phase and a mobile phase followed by recrystallization with a solvent or mixture of solvents to obtain highly pure Anastrozole.
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Page/Page column 14
(2008/06/13)
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- Dual aromatase-sulfatase inhibitors based on the anastrozole template: Synthesis, in vitro SAR, molecular modelling and in vivo activity
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The synthesis and biological evaluation of a series of novel Dual Aromatase-Sulfatase Inhibitors (DASIs) are described. It is postulated that dual inhibition of the aromatase and steroid sulfatase enzymes, both responsible for the biosynthesis of oestrogens, will be beneficial in the treatment of hormone-dependent breast cancer. The compounds are based upon the Anastrozole aromatase inhibitor template which, while maintaining the haem ligating triazole moiety crucial for enzyme inhibition, was modified to include a phenol sulfamate ester motif, the pharmacophore for potent irreversible steroid sulfatase inhibition. Adaption of a synthetic route to Anastrozole was accomplished via selective radical bromination and substitution reactions to furnish a series of inhibitory aromatase pharmacophores. Linking these fragments to the phenol sulfamate ester moiety employed SN2, Heck and Mitsunobu reactions with phenolic precursors, from where the completed DASIs were achieved via sulfamoylation. In vitro, the lead compound, 11, had a high degree of potency against aromatase (IC50 3.5 nM), comparable with that of Anastrozole (IC50 1.5 nM) whereas, only moderate activity against steroid sulfatase was found. However, in vivo, 11 surprisingly exhibited potent dual inhibition. Compound 11 was modelled into the active site of a homology model of human aromatase and the X-ray crystal structure of steroid sulfatase. This journal is The Royal Society of Chemistry.
- Jackson, Toby,Woo, L. W. Lawrence,Trusselle, Melanie N.,Chander, Surinder K.,Purohit, Atul,Reed, Michael J.,Potter, Barry V. L.
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p. 2940 - 2952
(2008/04/02)
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- PROCESS FOR PREPARING ANASTROZOLE
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A process for preparing anastrazole.
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Page/Page column 5
(2008/06/13)
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- IMPROVED PROCESS FOR HIGH PURITY ANASTROZOLE
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The present invention relates to an improved process for the preparation of anastrozole having enhanced purity from crude anastrozole having isomeric impurity content up to less than 1 %. The invention also relates to a pocess comprising steps of converting (3- cyanomethyl-5-methylphenyl) acetonitrile to 2-[(3-cyanodimethylmethyl)-5-methyl phenyl]- meiliyl propiononitrile (II) by C- alkylation, which is further converted into 2-[3-halomethyl- 5-cyanodimethyl methyl)phenyl] methyl propiononitrile (Ill) by radical bromination and further to crude anastrozole by reacting (III) with sodium salt of 1,2,4-triazole, purification of the crude anastrozole by preparing its acid addition salt, generating required final anaslrozole from the acid addition salt.
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Page/Page column 5
(2008/06/13)
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- Novel processes for preparing substantially pure anastrozole
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The present invention provides novel processes for purifying anastrozole, devoid of using liquid chromatography. The purification processes are via the isolated anastrozole salt forms, either by crystallization or by selective acidic extractions, and optionally in both cases, converting the purified anastrozole salt to anastrozole base. Also provided is an improved process for the synthesis of anastrozole, which is obtained by alkylating the isolated and purified starting material 3,5-bis(2-cyanoprop-2-yl)benzylbromide, the process being devoid of using toxic, hazardous and environmental unfriendly solvents and reagents.
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Page/Page column 8; 12
(2008/06/13)
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- Process for the preparation of anastrozole and intermediates thereof
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A process for the preparation of anastrozole is provided, the process comprising: (a) reacting 3,5-bis(1-cyano-1-methylethyl)benzyl halide with a 4-Z-1,2,4-triazole compound of the formula wherein Z is a protecting group to produce 2,2′-[5-(4-Z-1,2,4-triazolium-1-ylmethyl)-1,3-phenylene]di(2-methylpropionitrile) halide; and (b) deprotecting the 2,2′-[5-(4-Z-1,2,4-triazolium-1-ylmethyl)-1,3-phenylene]di(2-methylpropionitrile)halide to produce anastrozole. Also provided is anastrozole substantially free of its isomers.
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Page/Page column 5; 7
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF ANTICANCER DRUGS
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A process for preparing Anastrozole is provided. In the process the steps of a. combining 3,5-bis (2-cyanoisopropyl)toluene, a solvent selected from the group consisting of acetonitrile, dichloromethane and chlorobenzene, a brominating reagent selected from a group consisting of N-bromosuccinimide and l,3-dibromo-5,5-dimethylhydantoin, and 2,2'- azobis(2-methylpropionitrile); b. heating; c. combining with 1,2,4-triazole, a solvent selected from a group consisting of N-methylpyrrolidine, dimethylformamide, mixtures of NMP and DMF, dimethylsulfoxide, mixtures of DMSO and toluene, acetone, ACN, and tetrahydrofuran, a base selected from a group consisting of NaOH, KOH, K2CO3, and Na2CO3, and l,3-benzendiacetonitrile-5- (bromomethyl)-α, α, ?, ?- tetramethyl, at a temperature below -20°C are performed.
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Page/Page column 13
(2008/06/13)
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- Improved process for side-chain bromination of alkyl-benzenes
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A process for the side-chain bromination of alkylbenzenes according to Formula (I) wherein R1 is C1-C6-alkyl; R2 is H or C1-C6-alkyl which can be unsubstituted or substituted by one or more cyano groups; R3 is H or C1-C6-alkyl which can be unsubstituted or substituted by one or more cyano groups; comprising the steps of (1) dissolving the compound of Formula (I) in a solvent which is a nonaromatic non-halogenated hydrocarbon which can be substituted by one or more cyano groups; (2) adding a bromination agent selected from the group consisting of Br2 and N-bromoimides to the solution; and optionally (3) agitating the mixture at a temperature within the range of from room temperature to reflux temperature.
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- Process for side-chain bromination of alkylbenzenes
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A process for the side-chain bromination of alkylbenzenes according to Formula (I) wherein R1 is C1-C6-alkyl; R2 is H or C1-C6-alkyl which can be unsubstituted or substituted by one or more cyano groups; R3 is H or C1-C6-alkyl which can be unsubstituted or substituted by one or more cyano groups; comprising the steps of (1) dissolving the compound of Formula (I) in a solvent which is a non-aromatic non-halogenated hydrocarbon which can be substituted by one or more cyano groups; (2) adding a bromination agent selected from the group consisting of Br2 and N-bromoimides to the solution; and optionally (3) agitating the mixture at a temperature within the range of from room temperature to reflux temperature.
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Page/Page column 4; Fig. 1
(2010/11/23)
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- IMPROVED PROCESS FOR THE PREPARATION OF HIGH PURITY ANASTROZOLE
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Present invention discloses an improved process for the preparation of high purity anastrozole of formula-I (2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropio-nitrile) consisting of: (i) halogenation of 5, α, α, α', α'-pentamethyl-1,3-benzenediacetonitrile; (ii) reaction with sodium/potassium triazole; (iii) purification of crude anastrozole (containing more than 1% of triazole isomeric impurity) through salt formation; and (iv) isolation of pure anastrozole from its salts. It is observed that the removal of triazole isomeric impurity is possible only through a salt formation.
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Page/Page column 7-8
(2008/06/13)
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