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

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

Uses

Used in Pharmaceutical Industry:
3,5-Bis(2-cyanoprop-2-yl)benzyl bromide is used as an intermediate compound for the synthesis of Anastrozole (A637425), an aromatase inhibitor used in the treatment of breast cancer. It is specifically utilized in the production of α,α,α',α'-Tetramethyl-5-bromomethyl-1,3-benzenediacetonitrile (Anastrozole EP Impurity C), which is an impurity of Anastrozole (impurity D).
Used in Chemical Synthesis:
3,5-Bis(2-cyanoprop-2-yl)benzyl bromide may also be used as a building block or reagent in the synthesis of other organic compounds, particularly those with potential applications in the pharmaceutical, agrochemical, or materials science industries. Its unique structure and functional groups can be exploited to create a variety of novel molecules with specific properties and functions.

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

A process for synthesizing preparing anastrozole

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.

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.

How to use the Lasentec FBRM probe on manufacturing scale

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).

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.

Process for the Preparation of Pure Anastrozole

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.

Process for the Preparation of Pure Anastrozole

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).

PROCESS FOR THE PREPARATION OF PURE ANASTROZOLE

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.

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.

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.