120511-84-4

Basic information

• Product Name: 3,5-Bis(2-cyanoprop-2-yl)benzyl bromide
• Synonyms: 5-(BROMOMETHYL)-A,A,A,A-TETRAMETHYL-1,3-BENZENEDIACETONITRILE;5-BROMOMETHYL-A,A,A',A'-TETRAMETHYL-1,3-BENZENEDIACETONITRILE;5-(BROMOMETHYL)-ALPHA,ALPHA,ALPHA,ALPHA-TETRAMETHYL-1,3-BENZENEDIACETONITRILE;5-BROMOMETHYLTETRAMETHYL-1,3-BENZENEDIACETONITRILE;3,5-Bis(2-cyanoprop-2-yl)benzyl bromide;2,2-(5-BROMOMETHYL-1,3-PHENYLENE) DI(2-METHYLPROPIONONITRILE);2,2'-(5-BROMOMETHYL-1,3-PHENYLENE)-DI-(2-METHYLPROPIONITRILE);5-BROMOMETHYL-A,A,A',A'-TETRAMETHYL-1,3-BENZENEDIACETONITRIL
• CAS NO: 120511-84-4
• Molecular Formula: C₁₅H₁₇BrN₂
• Molecular Weight: 305.21
• EINECS: 1592732-453-0
• Product Categories: Anastrozole;Intermediate of Anastrozole;Methyl Halides;Phenyls & Phenyl-Het;Anastrazole;Aromatics;Impurities;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 120511-84-4.mol
• Article Data: 19

Chemical Properties

• Melting Point: 98-100°C
• Boiling Point: 379.996 ºC at 760 mmHg
• Flash Point: 183.615 ºC
• Appearance: Off-White Solid
• Density: 1.277 g/cm³
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• CAS DataBase Reference: 3,5-Bis(2-cyanoprop-2-yl)benzyl bromide(CAS DataBase Reference)
• NIST Chemistry Reference: 3,5-Bis(2-cyanoprop-2-yl)benzyl bromide(120511-84-4)
• EPA Substance Registry System: 3,5-Bis(2-cyanoprop-2-yl)benzyl bromide(120511-84-4)

Safety Data

• Hazardous Substances Data: 120511-84-4(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Solid

Uses

Different sources of media describe the Uses of 120511-84-4 differently. You can refer to the following data:
1. α,α,α’,α’-Tetramethyl-5-bromomethyl-1,3-benzenediacetonitrile (Anastrozole EP Impurity C) is an impurity of Anastrozole (A637425) (impurity D).
2. α,α,α’,α’-Tetramethyl-5-bromomethyl-1,3-benzenediacetonitrile (Anastrozole EP Impurity C) is an impurity of Anastrozole(impurity D).

Synthetic route

3,5-bis(2-cyanoprop-2-yl)toluene (120511-72-0) → 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4)

Conditions	Yield
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 2 - 2.5h; Heating / reflux;	87%
With N-Bromosuccinimide In dichloromethane for 4h; Product distribution / selectivity; UV-irradiation; Heating / reflux;	85%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 75 - 80℃; for 3h; Solvent; Reagent/catalyst;	85%

1,2,4-Triazole (288-88-0) + 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) → anastrozol (120511-73-1)

Conditions	Yield
With potassium tert-butylate In toluene at 9 - 21℃; for 4.5h;	100%
With tetrabutylammomium bromide; potassium hydroxide In water; toluene at 75 - 80℃; for 2h; Solvent; Temperature; Reagent/catalyst;	82%
With tetrabutylammomium bromide; potassium carbonate; potassium hydroxide In toluene at 85 - 90℃; for 5h;	47%

4-amino-1,2,4-triazole (584-13-4) + 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) → 4-amino-1-[3,5-bis(1-cyano-1-methylethyl)benzyl]-4H-1,2,4-triazolium bromide

Conditions	Yield
In acetonitrile for 12h; Reflux;	93%
In isopropyl alcohol at 0 - 85℃; for 10 - 10.5h;	65%
In isopropyl alcohol at 20 - 85℃;
In isopropyl alcohol at 80 - 85℃; for 5h;
for 3h; Reflux; Industrial scale;

2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) + sodium triazole (41253-21-8) → 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrochloride

Conditions	Yield
Stage #1: 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile; sodium triazole With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; Stage #2: With hydrogenchloride In DMF (N,N-dimethyl-formamide); water; toluene Product distribution / selectivity;	84%

2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) → 1,2-bis[3,5-bis(2-cyanoisopropyl)phenyl]ethane

Conditions	Yield
With magnesium; methyl iodide In tetrahydrofuran at 65 - 70℃; for 2h; Reagent/catalyst; Grignard Reaction; Inert atmosphere;	46.2%

2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) + sodium triazole (41253-21-8) → anastrozol (120511-73-1)

Conditions	Yield
Stage #1: 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile; sodium triazole In N,N-dimethyl-formamide at 45 - 50℃; for 4h; Stage #2: With hydrogenchloride; water at 50℃; pH=2; Stage #3: With ammonia In water at 0 - 5℃; pH=8 - 9;	34%
In N,N-dimethyl-formamide at 20℃; for 1h;	34%
In N,N-dimethyl-formamide at 20℃; for 1h;	34%

2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) + sodium triazole (41253-21-8) → 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrobromide (876514-43-1)

Conditions	Yield
Stage #1: 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile; sodium triazole With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; Stage #2: With hydrogen bromide In DMF (N,N-dimethyl-formamide); water; toluene

2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) + sodium triazole (41253-21-8) → 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrochloride + 2,2'-[5-(4H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methyl-propionitrile) hydrochloride

Conditions	Yield
Stage #1: 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile; sodium triazole With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 4h; Stage #2: With hydrogenchloride In toluene for 0.25h; Product distribution / selectivity;

1,2,4-Triazole (288-88-0) + 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) → 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrochloride + 2,2'-[5-(4H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methyl-propionitrile) hydrochloride

Conditions	Yield
Stage #1: 1,2,4-Triazole; 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile With potassium carbonate In DMF (N,N-dimethyl-formamide); isopropyl alcohol at 20℃; for 20h; Stage #2: With hydrogenchloride In toluene for 2h; Product distribution / selectivity;

2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) → anastrozol (120511-73-1)

Conditions	Yield
Stage #1: 1,2,4-Triazole With sodium hydroxide In 1-methyl-pyrrolidin-2-one at 20 - 60℃; for 14 - 55h; Stage #2: 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile In 1-methyl-pyrrolidin-2-one at -26 - -20℃; for 18 - 26h; Stage #3: With acetic acid In 1-methyl-pyrrolidin-2-one pH=6.5 - 7; Product distribution / selectivity;

2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) + (1-tritylimidazol-4-yl)carboxaldehyde (33016-47-6) → 2,2'-[5-(5-formylimidazol-1-yl)-1,3-phenylene]-di(2-methylpropiononitrile) (120512-62-1)

Conditions	Yield
With acetic acid In methanol; chloroform; water; acetonitrile

2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) + sodium triazole (41253-21-8) → 3,5-bis(2-cyanoprop-2-yl)toluene (120511-72-0) + α,α,α',α'-tetramethyl-5-(4H-1,2,4-triazol-4ylmethyl)-1,3-benzene-diacetonitrile (120511-92-4) + anastrozol (120511-73-1)

Conditions	Yield
In N,N-dimethyl-formamide at -10 - -5℃; for 0.75h; Product distribution / selectivity;

1,2,4-Triazole (288-88-0) + 2-[3-bromomethyl-5-(cyanodimethylmethyl)phenyl]-2-methylpropanenitrile (120511-84-4) → α,α,α',α'-tetramethyl-5-(4H-1,2,4-triazol-4ylmethyl)-1,3-benzene-diacetonitrile (120511-92-4) + anastrozol (120511-73-1)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 2h; Product distribution / selectivity; Reflux;
With potassium carbonate In toluene at 9 - 21℃; for 4.5h; Overall yield = 71.8 %; Overall yield = 42.14 g;

Upstream product

• 120511-72-0 3,5-bis(2-cyanoprop-2-yl)toluene 

Downstream Products

• 120511-73-1 anastrozol 
• 120511-92-4 α,α,α',α'-tetramethyl-5-(4H-1,2,4-triazol-4ylmethyl)-1,3-benzene-diacetonitrile 
• 120511-72-0 3,5-bis(2-cyanoprop-2-yl)toluene 
• 120512-62-1 2,2'-[5-(5-formylimidazol-1-yl)-1,3-phenylene]-di(2-methylpropiononitrile) 
• 876514-43-1 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrobromide 

Relevant articles and documents

Preparation method of anastrozole intermediate 3, 5 -bis (2 -cyanopropyl -2 -yl) bromotoluene

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.

METHOD FOR PREPARING ANASTROZOLE FOR PHARMACEUTICAL PURPOSES

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.

A process for the preparation of a benzylbromide intermediates

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.