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Process for the Preparation of Pure Anastrozole Field of Invention
5 The present invention relates to an improved process for preparing pure anastrozole. Moreover the process relates to alkylation of the isolated and purified 3,5-bis(2-cyanoprop-2-yl)benzylbromide as starting material, without the use of toxic, hazardous and environmentally unfriendly solvents.
10 Background of the Invention
Anastrozole is a common name for the chemically known substance 2,2'-[5-(1H-1,2,4-triazoi-l-ylmethylj-l^-phenylene^^-methylpropionitrile), represented by formula (I):

15
Anastrozole is a selective and potent non-steroidal drug which inhibits the action of the enzyme aromatase. It is used for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. 20 Anastrozole is further recognized and granted for treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown, locally advanced or metastatic breast cancer and also for adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.


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The synthesis of anastrozoie is described in U.S. Pat. Nos. 4935437 and RE 36617 ( a re¬issue of U.S. Pat. No.4935437 assigned to AstraZeneca Pharmaceuticals). These patents describe two synthetic routes for preparing anastrozoles one starting from methyl-3,5-dimethylbenzoate in a six-step process and the other started from 3,5-5 bis(bromomethyl)toluene in a three-step process. The second process is preferable because it is much shorter and easier to perform, however both processes involve a benzylic bromination stage with N-bromosuccinimide (NB§) in CCI4.
In the first process, bromination of methyl-3,5-dimethylbenzoate with N-bromosuccinimide 10 (NBS) in CCI4 affords a 3,5-bis(bromomethyl) compound, which is subsequently treated with potassium cyanide to afford a dinitrile compound. The dinitrile compound is alkylated, then reduced to the corresponding alcohol. The alcohol is converted to an alkyl chloride intermediate, and anastrozoie is then obtained by reaction of the latter compound with sodium triazole. The final product is purified by flash column chromatography, using a 15 repeated elution with a methanolxhloroform solvent mixture.
In the second process, the starting material, 3,5-bis(bromomethyl)-toluene, is reacted with potassium cyanide in dichloromethane in the preserve of a catalytic amount of tetrabutyiammonium bromide (TBAB) to obtain 2,2'-(5-methyI-1l3-phenylene)diacetonitrile.
20 The product is mixed with iodomethane and sodium hydrufe jn DMF to thereby obtain 2,2'-(5-methyl-1,3-phenylene)di(2-methylpropionitrile), (also referred to as 3,5-bis(2-cyanoprop-2-yl)toluene) which is further brominated using benzoyl peroxide and N-bromosuccinimide (NBS) in carbon tetrachloride. The mixture is refluxed for 2 hours, cooled, filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue obtained is
25 dissolved in DMF and sodium triazole is added. After completion of the reaction, anastrozoie is purified by flash column chromatography, eluting with ethyl acetate. The last part of this process is shown in Scheme 1 below.
Scheme I
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Thus, the bromomethyi intermediate in the process is not isolated or purified in either 15 process, but is directly converted to anastrozoie in situ. As a result of using the non¬isolated, non-purified intermediate, an impure final product is obtained.
Further, the use of a chromatographic solvent such as chloroform (being a carcinogenic solvent), the use of a solvent such as carbon tetrachloride (also being a carcinogenic 20 solvent) for the bromination reaction, and DMF for the alkylation reaction is disadvantageous with respect to industrial application.
US 20060189670 describes the preparation of anastrazole by reacting 3,5 bis-(1-cyano-1 methyl ethyl)benzylhalide with 4-Z-1,2,4-triazole.
25
US 2006/0035950 provides processes (scheme II) for purifying anastrozoie, avoiding the use of liquid chromatography. The purification processes are via the isolated anastrozoie salt forms, either by crystallization or by selective acidic extractions, and optionally in both cases, converting the purified anastrozoie salt to anastrozoie base. A process for the
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synthesis of anastrozole, which is obtained by alkylating the isolated, purified, 3,5-bis(2-cyanoprop-2-yl)benzyIbromide is also disclosed.

The above patent describes the preparation of 3,5-bis(2-cyanoprop-2-yl)benzyIbromide, which is carried out in a solvent of either dichloromethane (the yield is low), or acetonitriie (the yield is not reported) and purified (the yield reported in this process is low). There are
10 a number of steps involved in the synthesis of anastrozole, resulting in lower yield. For example, following alkylation to produce crude anastrozole, the US'950 process involves converting the crude anastrozole to a salt of anastrozole, isolating the salt of anastrozole, optionally recrystallising the salt of anastrozole, optionally converting the salt of anastrozole to anastrozole base and isolating the product.
15
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5 The bromination reaction as described in '950 can be carried out in a solvent selected from the group of ethyl acetate, acetone, dichloromethane, methyl acetate, isopropyl acetate, isopropyl acetoacetate, tert-butyl acetate and acetonitrile. However, it was found that in the presence of some solvents, the purity of the product was not high. The impurity 3,5-5 bis(cyanoprop-2-yl)benzyl bromide, a compound of formula (IV) formed during the reaction was found to an extent of 15-20% and other problems were encountered using some of these solvents which are susceptible to bromination.

10
The bromination reaction described in US '590 was followed by reflux for 4-5 hours. The US '950 inventors have found that longer reaction times cause increased levels of the impurity 3,5-bis(cyanoprop-2-yl)benzylbromide. Thus, the bromination process described in US2006/0035950 is not an efficient process to produce the product in high yield.
15 Furthermore, the purification of the crude anastrozole involves many steps, which makes the process less suitable for industrial application and reduces yield.
Because of the difficulties encountered in the process disclosed in the prior art, for example using carbon tetrachloride (CCl4) and DMF on an industrial scale, and the lower 20 yields, it would be highly desirable to develop a process for preparing anastrozole, which does not involve the use of carcinogenic solvents like carbon tetrachloride and DMF and which results in a high yield, high purity product.
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15

Anastrozole is administered in a 1mg dosage and it is a very expensive product. Thus, there is a constant need for developing a new process for its preparation, which provides good yield with high purity, making the process commercially viable. The process of the present invention provides anastrozole in good yield with high purity.
Object of the invention
The main object of the present invention is to provide an improved process for preparation of anastrazole with purity greater than 99.8%.
Summary of the Invention
The present invention provides a process for the preparation of anastrozole which comprises:
a) brominating 3,5-bis(2-cyanoprop-2-yl)toiuene (II) in an organic solvent using a brominating agent to obtain 3,5-bis(2-cyanoprop-2-yl)benzylbromide (III);


20
b) isolating and purifying the bromo intermediate (III) using an organic solvent;
c) 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
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1 ■-.,:■© ■.
d) isolating and purifying the anastrozole from an organic solvent.
Preferably, the bromination reaction of step a) is carried out at the reflux temperature of 5 the solvent used in step a). It has surprisingly been found that carrying out the refluxing for a period of time not longer than 3 hours reduces the formation of the impurity 3, 5-bis(cyanoprop-2-yl)benzyl bromide (IV)

10
Thus, according to another aspect of the present invention, there is provided a process for the preparation of anastrozole which comprises: a) brominating 3,5-bis(2-cyanoprop-2-yl)to!uene (II) in an organic solvent using a brominating agent to obtain 3,5-bis(2-15. 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; e) isolating and purifying the anastrozole


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from an organic solvent. Preferably, the organic solvent in the. brominating step is acetonitrile.
There is also provided by the present invention a process for preparing 3,5-bis(2-5 cyanoprop-2-yl)benzylbromide (III) which comprises brominating 3,5-bis(2-cyanoprop-2-yl)toluene (II) in an organic solvent using a brominating agent, heating the reaction mass to the reflux temperature of the organic solvent for a period of time no longer than 3 hours; and isolating and purifying the bromo intermediate (III) using an organic solvent to obtain 3,5-bis(2-cyanoprop-2-yl)benzylbromide (III). Preferably, the organic solvent in the 10 brominating step is acetonitrile.
Suitably, the refluxing is carried out for 3 hours. Preferably, the refluxing is carried out for 1 hour.
15 The preferred the organic solvent for use in step a) is acetonitrile. It has surprisingly been found that using acetonitrile as the bromination solvent is particularly effective in aiding the removal of the impurity (IV).
Thus, according to another aspect of the present invention, there is provided a process for 20 the preparation of anastrozole which comprises: a) brominating 3,5-bis(2-cyanoprop-2-yl)toluene (II) in acetonitrile using a brominating agent to obtain 3,5-bis(2-cyanoprop-2-yl)benzylbromide (III); b) isolating and purifying the bromo intermediate (III) using an organic solvent;c) 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 25 d) isolating and purifying the anastrozole from an organic solvent. Preferably, the bromination reaction mass is heated to the reflux temperature of the organic solvent for a period of time no longer than 3 hours.
There is also provided by the present invention a process for preparing 3,5-bis(2-30 cyanoprop-2-yi)benzylbromide (ill) which comprises brominating 3,5-bis(2-cyanoprop-2-
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9 yl)toluene (II) in acetonitrile using a brominating agent, and isolating and purifying the bromo intermediate (III) using an organic solvent to obtain 3,5-bfs(2-cyanoprop-2-yl)benzyibromide (III). Preferably, the bromination reaction mass is heated to the reflux temperature of acetonitrile for a period of time no longer than 3 hours. 5
Using acetonitrile as the organic solvent in the brominating step and employing the step of heating the bromination reaction mass to the reflux temperature of the organic solvent for a period of time no longer than 3 hours is particularly preferred.
10 The brominating agent may be an N-halosuccinimide. Preferably, the N-halosuccinimide is N-bromosuccinimide.
The organic solvent used in the purification of the brominated intermediate may be selected from the group consisting of isopropyl alcohol, n-heptane, n-hexane, toluene and 15 mixtures thereof. Preferably, the organic solvent is a mixture of isopropyl alcohol and n-heptane.
The isolation of the brominated intermediate may involve quenching the reaction mass with water, concentrating the quenched reaction mass to a residue, charging an organic 20 solvent such as methylene chloride to the residue, filtering the insolubles and washing with the solvent. The organic layer may be washed with a sodium sulfite solution, followed by a sodium chloride solution then a sodium chloride solution. The layer may then be washed with water, dried and concentrated to a residue.
25 The base used in the alkylating step may be selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate and mixtures thereof. Preferably, the base is potassium carbonate and potassium hydroxide, and the potassium hydroxide is in powdered form.
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10 The phase transfer catalyst may be a quaternary ammonium salt for example a tetraalkyl ammonium halide, or a crown ether. The alkyl group is an alkyl of 1 to 18 carbon atoms. Preferably, the alkyl is methyl, ethyl or propyl. The halide may be chloro, bromo or iodo. For example, the tetraalkyl ammonium halide may be Me4NCI, Me4NBr, Me4NI, EUNBr, n-5 Pr4NCl, n-Pr4N! or n-Bu4NBr. Suitably, the tetraalkyl ammonium halide Is tetrabutylammonium bromide.
The organic solvent used in the alkylating step may be selected from the group consisting of toluene, DMF, acetonitrile and cyclohexane. Preferably, the organic solvent is toluene. 10
The 1,2,4-triazole is 1,2,4-triazole or a salt thereof, for example an alkali metal salt. Optionally, the 1,2,4-triazole is the sodium salt of 1,2,4-triazole.
The organic solvent used in the step of purifying anastrozole may be a water immiscible 15 solvent or a mixture of water immiscible solvents. Surprisingly, it has been found that a mixture of ethylacetate and diisopropylether is particularly preferred for the isolation and purification of anastrozole. This combination of solvents is particularly effective in aiding the removal of impurities, especially those formed during the bromination step.
20 Thus, according to another aspect of the present invention, there is provided 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) isolating and purifying the bromo intermediate (III) using an organic solvent; c) alkylating the bromo intermediate in the presence of a base,
25 optionally a phase transfer catalyst, a 1,2,4-triazole and an organic solvent to obtain anastrozole; d) isolating and purifying the anastrozole from ethylacetate and diisopropylether. Preferably, the organic solvent in the brominating step is acetonitrile. Preferably, the bromination reaction mass is heated to the reflux temperature of the organic solvent for a period of time no longer than 3 hours.
30
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Furthermore, according to another aspect of the present invention, there is provided a process for purifying crude anastrozole comprising crystallising anastrozole from ethylacetate and diisopropylether. Suitably, the ethylacetate and diisopropylether are charged to the crude anastrozole, the mixture is optionally stirred for example for a period 5 of time ranging from 10 minutes to 1 hour, suitably for around 30 minutes, chilling the mixture for example to a temperature ranging from about 0 to about 10°C, suitably from about 0 to about 5°C, and isolating the solid product, for example by filtration, washing and drying under vacuum.
10 In an embodiment, none of the organic solvents used in any of the steps is carbon tetrachloride.
In an embodiment, benzoyl peroxide is present in the bromination step.
15 In another embodiment, an acid is present in the bromination step. The acid may be sulphuric acid or acetic acid. Preferably, the acid is sulphuric acid. When an acid is present in the bromination step, the refluxing of the brominatton reaction mass may be carried out in a shorter time, for example in one hour. This shorter time is particularly preferred as it aids in reducing the formation of impurity (IV).
20
Thus, a particularly preferred embodiment of the process for the preparation of anastrozole according to the present invention is one in which the organic solvent used in the brominating step is acetonitriie, the bromination reaction mass is heated to the reflux temperature of the organic solvent for a period of time no longer than 3 hours, the
25 brominating agent is N-bromosuccinimide, an acid is optionally present during the bromination step, the organic solvent used in the purification of the brominated intermediate is a mixture of isopropyl alcohol and n-heptane, the organic solvent used in the alkylation step is toluene and the organic solvent used in the purification of anastrozole is a mixture of ethylacetate and diisopropylether.
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In an embodiment, the purified product of the bromination reaction contains the impurity 3,5-bis(cyanoprop-2-yl)benzyl bromide (IV) in an amount ranging from 5 to 8%.
In a .further embodiment, the purified product of step b) is substantially free from the 5 impurity 3, 5-bis(cyanoprop-2-yl)benzyl bromide (IV)

^CHBr2
CH3 H3CPCN
w
The anastrozole prepared according to the process of the present invention may be 10 obtained with purity greater than or equal to 99.8%. Typically, the anastrozole is obtained with purity of 99.8%. Desirably, the anastrozole is obtained with purity of 99.8%. Anastrozole prepared according to the process of the present invention forms another aspect of the present invention.
15 According to another aspect of the present invention, there is provided anastrazoie having a purity greater than or equal to 99.8%. In an embodiment, the anastrozole has a purity of 99.8%. Preferably the anastrozole has a purity of 99.9%.
Detailed Description of the Invention 20
In an embodiment, the process of the present invention is as shown in scheme III.
Scheme III
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According to one embodiment of the present invention as depicted in scheme III, the starting material 3J5-bis(2-cyanoprop-2-yl)toluene (formula II), is brominated using N-5 bromosucccinimide (NBS) to the benzyl bromide intermediate 3,5-bis(2-cyanoprop-2-y1)benzylbromide (formula III) in the presence of benzoyl peroxide in acetonitrile.
The bromination reaction is carried out at reflux temperature for not more than 3 hours after which time the impurity 3,5-bis(cyanoprop-2-yl)benzylbromide, a compound of 10 formula (IV), is formed in a substantially low percentage. In particular, impurity (IV) is formed in an amount ranging from about 5 to 8 %. in US '950, impurity (IV) is formed to an extent ranging from about 40 to 50% because of the solvent used and the longer reaction time.
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IV
Surprisingly it was found that when bromination is carried out in the presence of an acid such as sulphuric acid or acetic acid, the formation of the dibromo impurity IV is minimized and the reaction goes to completion in less than 1 hour. The product is formed in 110% 5 w/w yield.
In another embodiment of the present invention, the small amount of the impurity of formula (IV) generated in the bromination step is efficiently removed by purifying the bromo intermediate using a suitable solvent, which results in 3,5-bis(cyanoprop-2-yl)benzyl 10 bromide with purity greater than 90%. The suitable solvent used for purifying the bromo compound is an organic solvent and may be selected from the group consisting of isopropyl alcohol, n-heptane, n-hexane, toluene and mixtures thereof. A particularly preferred solvent is a mixture of isopropyl alcohol and n-heptane.
15 In yet another embodiment of the present invention, the purified bromo compound (formula (III)) is alkylated with 1,2,4-triazole in a suitable solvent using a suitable base in the presence of a phase transfer catalyst such as tetrabutyl ammonium bromide to obtain anastrozole, which is further purified using column chromatography, followed by precipitation/crystallization using ethyl acetate and diisopropy! ether to obtain pure
20 anastrozole in high yield.
Suitable solvents used for the above alkylation reaction are selected from the group consisting of toluene, DMF, acetonitrile and cycfohexane, preferably toluene.

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15 Suitable bases used are selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate and mixtures thereof, preferably potassium carbonate and powdered potassium hydroxide. 5
The process of the present invention affords anastrozole in high yield and high purity, the purity of the pure anastrozole obtained may be measured by HPLC.
The anastrozole prepared by the present invention has purity greater than or equal to 10 99.8%. In particular, anastrozole prepared by the present invention may have purity of 99.9%.
The details of the invention are given in the following examples, which are provided for illustration only and therefore these should not be construed to limit the scope of the 15 present invention in any manner.
Examples
Example 1 20 Preparation of 3,5-bis (2-cyanoprop-2-yl) benzyl bromide, compound of formula(lll)
Acetonitrile (about 10 Its), 3,5-bis(2-cyanoprop-2-yl)toluene (1.0 kg), benzoyl peroxide (23 g) and sulphuric acid (10 g) were charged and heated to 50-55°C. To this N-bromosuccinimide (1000 g) was added over a period of 3 hours, maintained for 30
25 minutes, then the termperature was slowly raised to reflux (75-80°C) and maintained for 1 hour. After reaction completion, the mass was cooled to 25-30°C, water (25 ml) was added and concentrated under vacuum to a residue at a temperature less than 60°C. The contents were cooled to 25-30°C, methylene choride (2500 ml) was charged, chilled to 10-15°C, the insolubies were filtered and washed with chilled methylene chloride (150 ml).
30 The combined methylene chloride layer was washed with 10% sodium sulphite solution
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16 (300 ml), followed by washing with 10% sodium bicarbonate solution (300 ml) and 10% sodium chloride solution (300 ml). The methylene chloride layer was finally washed with water (300ml), dried over sodium sulphate and concentrated to a residue under vacuum at 35-40°C. To this residue charged isopropyl alcohol followed by n-heptane, heated to 50-5 55°C, maintained for 30 minutes then slowly cooled to 25-30°C and stirred for 1 hour. The material so obtained was filtered, washed with n-heptane (250 ml).
Purification:
Isopropyl alcohol (400 ml) and n-heptane (5 Itrs.) were charged to the above material, the 10 contents were heated to 50-55°C, maintained for 30 minutes, cooled to 25-30°C, stirred for 1 hour at 25-30°C, filtered, washed with n-heptane (200ml) and dried under vacuum at 35-40°C to give 3,5-bis(2-cyanoprop-2-yl)benzyl bromide (1.1 kg, 110 % yield (w/w), 81.6 mol% yield, 96% HPLC purity).
15
Example 2
Preparation of 3,5-bis (2-cyanoprop-2-yl)benzylbromide, compound of formula (IN)
Acetonitrile(1300 ml), 3,5-bis(2-cyanoprop-2-yf) toluene (100 g), benzoyl peroxide (2.3 g)
20 and acetic acid (1.2 ml) were heated to 50-55°C. To this, N-bromosuccinimide (100 g) was
added over a period of 3 hours, maintained for 30 minutes, then the temperature was
siowly raised to reflux (75-80°C) and maintained for 3 hours. After reaction completion, the
mass was cooled to 25-30°C, water (2.5 ml) was added and concentrated under vacuum
to residue at a temperature lower than 60°C. The contents were cooled to 25-30°C,
25 methylene chloride (250 ml) was charged, chilled to 10-15°C, and the insolubles were
filtered and washed with chilled methylene chloride (15 ml). The combined methylene
chloride layer was washed with 10% sodium sulphite solution (30 ml), followed by a wash
with 10% sodium bicarbonate solution (30 mi) and 10% sodium chloride solution (30 ml).
The methylene chloride layer was finally washed with water (30 ml), dried over sodium
30 sulphate and concentrated to residue at 35-40°C. To this residue, isopropyl alcohol (30 ml)
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17 and n-heptane (490 ml) were charged, heated to 50-55°C, maintained for 30 minutes, stowty mooted to 25-30°G and stored for 1 hour. The metwal so obtesusd was ffered and > washed with n-heptane (25 ml).
5 Purification :
To the above material, isopropyl alcohol (240 ml) and n-heptane (240 ml) were charged, the contents were heated to 55-60°C for dissolution then allowed to cool to 40-44°C, filtered, washed with n-heptane (25 ml) and dried under vacuum at 35-40°C to give 3,5-bis (2-cyanoprop-2-y1)benzyl bromide (81 g, 60 mol% yield, 95 % HPLC purity). 10
Example 3
Preparation of 2,2,-[5-(1H-1f2,4-triazol-1-yl-methyl)-1,3-phenylene]-di(2-methyl
propionitrile), compound of formula (I) [ANASTROZOLE]
15 Toluene (1000 ml), 1,2,4-triazole (27 g), potassium carbonate (110 g), powdered potassium hydroxide (20 g), tetrabutyl ammonium bromide (7 g) and 3,5-bis(2-cyanoprop-2-yl) benzyl bromide (100 g) were charged, heated to 85-90°C and maintained for 5 hours. After reaction completion, the mass was cooled to 20-25°C, water (500 ml) was charged and the toluene layer was separated, the aqueous layer was extracted using toluene (300
20 ml), the toluene layer was combined, washed using water (500 ml) and the toluene layer dried over sodium sulphate. The toluene layer was concentrated under vacuum to residue at 50-55°C, isopropyl alcohol (18.8 ml) was charged followed by n-heptane (450 ml), the contents were stirred for 1 hour at 25-30°C, the contents were chilled to 0-5°C, maintained for 45 minutes, and the resulting material was filtered and washed with n-heptane (25 ml).
25
Purification:
The above material was loaded on a Silica gel column, eiuted with methylene chloride followed by the polarity being increased (to an extent of 30%) using ethyl acetate. The pure fractions containing anastrozole were concentrated to residue at 40-45DC, cooied to
30 20-25°C, methanol (420 ml) was charged, stirred for dissolution, clarified over hyflo and


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concentrated to residue under vacuum at 40-45°C. The contents were cooled to 20-25°C, ethyl acetate (13.8 ml) folfowed by diisopropyl ether (445 mf) was charged, stirred for 30 minutes, chilled to 0-5°C, maintained for 30 minutes, filtered, washed with diisopropyl ether ( 50 mi) and dried under vacuum at 40-45°C to give the title compound anastrozoie (45 g, 5 47 mol.% yield, 99.9% HPLC purity).
It will be appreciated that the invention may be modified within the scope of the appended claims.
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19 Claims
1. A process for the preparation of anastrozole which comprises:
5 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);

10 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;
15 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. 20 2. A process according to claim 1, wherein the refluxing is carried out for 3 hours.

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3. A process, according to claim 1, wherein the refluxing is carried out for 1 hour.
4. A process according to any preceding ciaim, wherein the organic solvent used in 5 step a) is acetonitrile.
5. A process according to any preceding claim, wherein the brominating agent is an N-
hafosuccinimide.
10 6. A process according to claim 5, wherein the N-halosuccinimide is N-bromosuccinimide.
7. A process according to claim 1, 2 or 3, wherein the organic solvent used in step a)
is acetonitrile and the brominating agent is N-bromosuccinimide.
15
8. A process according to any preceding claim, wherein the organic solvent used in
step c) is selected from the group consisting of isopropyl alcohol, n-heptane, n-hexane,
toluene and mixtures thereof.
20 9. A process according to any preceding claim, wherein the organic solvent used in step c) is a mixture of isopropyl alcohol and n-heptane.
10. A process according to claim 1, 2 or 3, wherein the organic solvent used in step a)
is acetonitrile, the brominating agent is N-bromosuccinimide and the organic solvent used
25 in step c) is a mixture of isopropyl alcohol and n-heptane.
11. A process according to any preceding claim, wherein the organic solvent used in
step d) is selected from the group consisting of toluene, DMF, acetonitrile and
cyclohexane.
30
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12. A process according to any preceding claim, wherein the organic solvent used in
step d) is toluene.
13. A process according to claim 1, 2 or 3, wherein the organic solvent used in step a)
5 is acetonitrile, the brominating agent is N-bromosuccinirnide, the organic solvent used in
step c) is a mixture of isopropyl alcohol and n-heptane and the organic solvent used in step d) is toluene.
14. A process according to any preceding claim, wherein the base used in step d) is
10 selected from the group consisting of potassium carbonate, sodium carbonate, sodium
hydroxide, potassium hydroxide, sodium bicarbonate potassium bicarbonate and mixtures thereof.
15. A process according to claim 14, wherein the base used in step c) is potassium
15 carbonate and potassium hydroxide.
16. A process according to claim 15, wherein the potassium hydroxide is in powdered
form.
20 17. A process according to any preceding claim, wherein, if present, the phase transfer catalyst is a tetraalkyl ammonium halide or a crown ether,
18. A process according to claim 17, wherein the tetraalkyl ammonium halide is
tetrabutylammonium bromide.
25
19. A process according to any preceding claim, wherein the triazoie used in step d) is
1 ,2,4-triazole or sodium triazoie.
20. A process according to any preceding claim, wherein the organic solvent used in
30 step e) is a water immiscible solvent.
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22
21. A process according to claim 20, wherein the organic solvent used in step e) is a mixture of ethylacetate and diisopropylether.
5 22. A process according to any one of claims 1 to 3 or 14 to 19, wherein the organic solvent used in step a) is acetonitrile, the brominating agent is N-bromosuccinimide, the organic solvent used in step c) is a mixture of isopropy! alcohol and n-heptane, the organic solvent used in step d) is toluene and the organic solvent used in step e) is a mixture of ethylacetate and diisopropylether. 10
23. A process according to any preceding claim, wherein none of the organic solvents
is carbon tetrachloride.
24. A process according to any preceding claim, wherein benzoyl peroxide is present in 15 step a).
25. A process according to any preceding claim, wherein an acid is present in step a).
26. A process according to claim 25, wherein the acid is sulphuric acid or acetic acid. 20
27. A process according to claim 26, wherein the acid is sulphuric acid.
28. A process according to any preceding claim, wherein the purified product of step c)
is substantially free from 3, 5-bis(cyanoprop-2-yl)benzyl bromide (IV)
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PCT/GB2007/003942


29. A process according to any one of claims 1 to 27, wherein the purified product of
step c) contains 3, 5-bis(cyanoprop-2-yf)benzyl bromide (IV) in an amount ranging from 5
5 to 8%.
30. A process according to any preceding claim, wherein the anastrozole in step e) is
obtained with purity greater than 99.8%.
10 31. Anastrozole having a purity greater than or equal to 99.8%.
32. Anastrozole according to claim 31, having a purity of 99.8%.
33. Anastrozole according to claim 32, having a purity of 99.9%. 15
34. A process for the preparation of anastrozole as substantially described herein with
reference to the foregoing examples 1 to 3.
35. Anastrozole substantially as herein described with reference to the foregoing
20 example 3.
15 MAY 2009