120511-74-2

Usage

Uses

Used in Pharmaceutical Industry:
5-Methyl-1,3-benzenediacetonitrile is used as an intermediate for the synthesis of Anastrozole, an aromatase inhibitor. It plays a crucial role in the production of this antineoplastic drug, which is used to treat various types of cancer, particularly breast cancer. The compound's chemical properties allow it to be a key component in the development of effective cancer treatments.
Used in Antineoplastic Applications:
As a precursor to Anastrozole, 5-Methyl-1,3-benzenediacetonitrile contributes to the development of antineoplastic drugs. Anastrozole, the final product, is used to inhibit the aromatase enzyme, which is responsible for converting androgens to estrogens. By inhibiting this enzyme, Anastrozole helps to reduce estrogen levels in the body, thereby slowing down the growth of hormone receptor-positive breast cancer cells.

InChI:InChI=1/C11H10N2/c1-9-6-10(2-4-12)8-11(7-9)3-5-13/h6-8H,2-3H2,1H3

Upstream product

• 19294-04-3 3,5-bis(bromomethyl)toluene 
• 64-17-5 ethanol 
• 151-50-8 potassium cyanide 
• 143-33-9 sodium cyanide 

Downstream Products

• 76935-61-0 2-(3,5-dimethylphenyl)ethylamine 
• 120511-72-0 3,5-bis(2-cyanoprop-2-yl)toluene 
• 46208-52-0 3,5-bis(2-aminoethyl)toluene 

Relevant academic research and scientific papers

Process for the Preparation of 2,2'-[5-(1H-1,2,4-Triazole-1-Ylmethyl) -1,3-Phenylene] Di (2-Methylpropionitrile)

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.

Exploiting protein fluctuations at the active-site Gorge of human cholinesterases: Further optimization of the design strategy to develop extremely potent inhibitors

Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.

PROCESS FOR THE PREPARATION OF 2,2’-[5-(1,2,4-TRIAZOLE-1-YLMETHYL) -1,3-PHENYLENE] DI (2-METHYLPROPIONITRILE).

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.

Dual aromatase-sulfatase inhibitors based on the anastrozole template: Synthesis, in vitro SAR, molecular modelling and in vivo activity

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.

Process for the preparation of anastrozole and intermediates thereof

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.

Improved process for side-chain bromination of alkyl-benzenes

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.

Process for side-chain bromination of alkylbenzenes

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.

(SUBSTITUTED ARALKYL) HETEROCYCLIC COMPOUNDS

A (substituted-aralkyl)heterocyclic compound of the formula I wherein R1 is an azido, carbamoyl, cyano, formyl, hy-droxy or nitro radical, a 1-6C 1-hydroxyalkyl, alkoxy, alkylcarbamoyl, alkylthio, alkylsulphinyl or alkylsulphonyl radical, a 2-cyanoethyl radical, optionally bearing one to four 1-6C alkyl substituents, or a 2-6C alkanoyl, halogenoalkanoyl, alkanoyloxy, alkanoylamino, dialkylcarbamoyl or alkoxycarbonyl radical; R2 and R3, which may be the same or different, are each a hydrogen atom, a 1-6C alkyl, dueterioalkyl or halogenoalkyl radical, or a phenyl or phenyl(l-6C alkyl) radical, in each of which the phenyl may optionally bear one or more substituents; or R2 and R3, together with the carbon atom to which they are attached, may form a 3- to 6-membered ring; or R1R2R3C- is a 1,1-dicyanoethyl or trifluoromethylsulphonyl radical; R4 is a hydrogen or halogen atom, a cyano or nitro radical or a 1-6C alkyl or halogenoalkyl radical; R5 has any of the values de-fined above for the group RIR2R3C but is not necessarily the same as R1R2R3C, or has any of the values de-fined above for R4 but is not necessarily the same as R4, or is a carbamoyl, 1-pyrrolidinyl-carbonyl, piperidino-carbonyl, morpholinocarbonyl or nitro radical, a 1-6C alkoxy or halogenoalkoxy radical or a 2-6C alkanoyl or alkoxy-carbonyl radical; A is a methylene or ethylene radical optionally bearing one or more substituents selected from deuterium and halogen atoms, carbamoyl, cyano and hydroxy radicals, 1-6C alkyl and alkoxy radicals, and 2-6C alkanoyloxy radicals provided that when A is linked to R through a nitrogen atom thereof, it may not bear a hydroxy, alkoxy or alkanoyloxy sub-stituent on the carbon atom adjacent to such nitrogen atoms; and R6is a lH-l,2,4-triazol-l-yl, 4H-l,2,4-triazol-4-yl, IH-imidazol-1-yl, 5-cyano-lH-imidazol-l-yl, 3-pyridyl or 5-pyrimidinyl radical, or a IH-imidazol-1-yl radical, bearing at the 5-position thereof a 1-6C alkyl substituent which is itself optionally substituted by one or more carbamoyl, cyano, hydroxy or 2-6C alkoxycar-bonyl radicals; and provided that when R2, R3, R4 and R5 are hydrogen, A is a methylene radical and R6 is a 3-pyridyl radical, R1 is not a cyano, hydroxy or hydroxymethyl radical, and when R1 is a hydroxy radical, R3, R4 and R5 are hydrogen, A is a methylene radical and R6 is 3-pyridyl, R2 is not a methyl or a 2-chloro-1-methylethyl radical, and provided that when R1 is a methoxycarbonyl radical, R2, R3, R4 and R5 are hydrogen and A is a methylene radical, Ri is not a IH-imidazol-a1-yl radical; and the pharmaceutically acceptable acid addition salts thereof