FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
AN IMPROVED PROCESS FOR THE PREPARATION OF ANASTROZOLE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALLY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides an improved process for the preparation of anastrozole.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides an improved process for the preparation of anastrozole.
Anastrozole of formula I is chemically known as a,a,a',a'-Tetramethyl-5-(1/-/-1,2,4-triazol-l-ylmethyl 1,3-benzenediacetonitrile. Anastrozole is a selective and potent non-steroidal drug, which inhibit the action of the enzyme aromatase, and is marketed for the treatment of advanced breast cancer.

Formula I
U.S. patent No. RE 36617 disclosed the processes of preparation of anastrozole. This includes two synthetic routes for preparing anastrozole, one starting from methyl 3,5-dimethylbenzoate and the other from 3,5-bis (bromomethyl) toluene.
Several other processes for the preparation of anastrozole are disclosed in US 20060035950; US 20060189670; US 20060217569; US 20060276657; US 20070217569 patent applications and PCT Patent application Nos. WO 2005105762; WO 2006000836; WO 2006108155.
The present inventors have now developed an improved process for the preparation of anastrozole. The process of present invention avoids prior art use of hazardous and expensive reagents such as sodium hydride for the conversion of 3,5-bis (cyanomethyl) toluene to 3, 5-bis (2-cyanoprop-2-yl) toluene. Further the
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process of present invention avoids use of carbon tetrachloride for the conversion of 3, 5-bis (2-cyanoprop-2-yl) toluene to anastrozole. The process of present invention is easily scalable and provides good yield.
In one of the aspect of the present invention there is provided a process for the preparation of 3,5-bis (2-cyanoprop-2-yl) toluene intermediate, useful in the preparation of anastrozole. The process includes step of:
a) reacting 3,5-bis (cyanomethyl) toluene with dimethyl sulfate in presence of alkali metal base,
b) isolating 3,5-bis (2-cyanoprop-2-yl) toluene from the reaction mass thereof.
In another aspect of the present invention there is provided a process for preparation of anastrozole. The process includes step of:
a) reacting 3,5-bis (2-cyanoprop-2-yl) toluene with brominating agent in an non halogenated solvent to get a, a, a', a'-tetramethyl-5-bromomethyl-1, 3-benzene diacetonitrile,
b) converting a.a.a'.a'-tetramethyl-S-bromomethyl-l, 3-benzene diacetonitrile to anastrozole and its isolation from the reaction mixture thereof.
The 3, 5-bis (2-cyanoprop-2-yl) toluene can be prepared by addition of 3,5-bis (cyanomethyl) toluene with methylating agent such as dimethyl sulfate, iodomethane and the like in high boiling polar aprotic solvent in the presence of alkali metal base at temperature of 2-6°C. High boiling polar aprotic solvent selected from the group consisting of dimethyl sulphoxide, dimethyl formamide and the like. The Alkali metal base includes but not limited to lithium hydroxide, sodium hydroxide and potassium hydroxide.
The 3,5-bis (2-cyanoprop-2-yl) toluene is reacted with brominating agent in non-halogenated solvent such as nitro benzene, acetonitrile and the like in presence of benzoyl peroxide at about 100° C. After the completion the
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a,a,a\a-tetraethyl-5-bromomethyl-1,3-benzene diacetonitrile was isolated
from the reaction mixture thereof.
The a.a.a'.a'-tetramethyl-5-bromomethy-1,3-benzene diacetonitrile is then converted to anastrozole using phase transfer catalyst by the methods- known in the art.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE Preparation of 3, 5 bis (2-cyanoprop-2-yl) toluene
Potassium hydroxide (1.98 g) and dimethyl sulfoxide (25 ml) were stirrred under nitrogen atmosphere at 2-6°C. To the resulting mixture, a solution of 3,5-bis (cyanomethyl) toluene (500 mg) in dimethyl sulfoxide (10 ml) and solution of Dimethyl sulfate (2.75 ml) in dimethyl sulfoxide (10 ml) were added simultaneously over the period of 40-45 minutes at temprature of 5° C. After completion of addition temperature was raised to 25°C and reaction mass stirred for half an hour for the completion of reaction. The 50 ml of water was added to the reaction mass the solid obtained was filtered and dissolved in ethyl acetate (10 ml). The titled product was precipitated by addition of n-hexane (40 ml) and isolated. Yield = 0.52 g
Preparation of a,a,a',a'-tetramethyl-5-bromomethyl-1,3-benzenediaceto nitrile 3,5 bis (2-cyanoprop-2-yl) toluene (1.0 g) was dissolved in nitrobenzene (25.0 ml). To this benzoyl peroxide (25 mg) was added followed by addition of N-bromosuccinimide (800 mg). The reaction mixture was heated to 100°C to reach on completion. Nitrobenzene was removed under reduced pressure and the residue dissolved in ethyl acetate (5 ml). The tilted compound was isolated by addition of n-hexane (25 ml) and isolated.
Yield = 0.97 g
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WE CLAIM:
1. A process for the preparation of 3,5-bis (2-cyanoprop-2-yl) toluene intermediate,
useful in the preparation of anastrozole. The process comprising:
a) reacting 3,5-bis (cyanomethyl) toluene with dimethyl sulfate in presence of alkali metal base,
b) isolating 3,5-bis (2-cyanoprop-2-yl) toluene from the reaction mass thereof.

2. A process of claim 1, wherein the reaction of 3,5-bis (cyanomethyl) toluene with dimethyl sulphate is carried out in high boiling polar aprotic solvent includes dimethyl sulphoxide, dimethyl formamide and the like
3. A process of claim 1, wherein the alkali metal base includes potassium hydroxide, sodium hydroxide lithium hydroxide and the like.
4. A process for preparation of anastrozole. The process comprises of:

a) reacting 3,5-bis (2-cyanoprop-2-yl) toluene with brominating agent in an non halogenated solvent to get a, a, a', a'-tetramethyl-5-brornomethyl-1, 3-benzene diacetonitrile,
b) converting a,a,a',a'-tetramethyl-5-bromomethyl-1, 3-benzene diacetonitrile to anastrozole and its isolation from the reaction mixture thereof.
5. A process of claim 4, wherein the non-halogenated solvent is nitrobenzene,
chlorobenzene and the like
6. A process of claim 6, wherein the brominating agent is N-bromosuccinimide
Dated this 30th day of Mar, 2007

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