FIELD OF THE INVENTION
The field of the invention relates to the preparation of highly pure anastro/.ole in good yields.
BACKGROUND OF THE INVENTION
Anastrozolc of formula I is a potent and selective non-steroidal inhibitor of the aromata.se (oestrogen synthetase) system, which converts adrenal androgens to oestrogens in peripheral tissue.
(Formula Removed)
Anastrozolc (INN. trade name: Arimidex-S) is indicated in the treatment of breast cancer in post-menopaiisal women. It is used both in adjuvant therapy (i.e. following surgery) and in metastatic breast cancer. It has the effect of decreasing the amount of estrogen that the body makes and is chemically known as a. a. a', a'-tetrametln 1-5-(1H-1.2.4-triazol-1 -yl methyl)-1.3-benzenecliacetonitrile.
Anastrozole is first disclosed in US 4.935.437 and mainly two routes have been discussed to prepare anastrozole. According to first route, the process eompriseN bromination of compound of formula 11 namely 2,2"-(5-mcthyl-l .3-phen\)cne)-di-(2-methyl propionitrile) (Formula Removed)

in carbon tetrachloride using A'-bromosuccinhnide in the presence of catalyst benzoy' peroxide to prepare bromomethyl derivative of formula III. (Formula Removed)

The bromometh} I derivative is further condensed with 1.2.4- triazole sodium in dimethylformamicle to get crude anastrozole. The crude anastrozole is purified b\ flash column chromatography and further crystallized in ethyl acetate-'cyclohexane to get pure anastrozole.
The compound of formula II is prepared by treating 3.5-bis(brornomethy]) toluene of formtila IV(Formula Removed)

with potassium cyanide in dichloromethane and in presence of tetrabut\ lammonium bromide to set diacetonitrile derivative of formula V. (Formula Removed)

The diacetonitrile derivative is purified by flash column chromatography and crystallized in carbon totrachloridc to get pure 2,2-(5-methyl-l,3-phenylcne) diacetonitrile.
The compound of formula V is further methylated with methyl iodide in diinethylformamide and in presence of strong base such as sodium hydride anil finally crystallized in carbon tetrachloricle to get compound of formula 11.
:urthermore. second route comprises reacting chloromethyl derivative of formula IlIa
(Formula Removed)

with 1.2.4- triazoic sodium in acctonitrile thereafter solvent is removed and the resulting residue is partitioned between ethyl acetate and aqueous potassium hydrogen carbonate. The organic phase is separated and dried to gel a mixture of anastrozole and its isomer. i.e. isoanastrozole of formula VI. (Formula Removed)

The isomeric mixture is separated by Hash column chromatography to gel pure anastrozole.
US patent application 2006/0035950 discloses a process for the preparation of pure anastrozole by reacting bromomethyl derivative of formula III with sodium triazole under basic conditions and the resulting crude anastrozolc is purified via anastrozole acid addition salt such as hydrocbloridc or hydrobromi.de salt. Generally crude anastrozole in toluene is treated with aqueous acidic solution of sodium sulfate and sulfuric acid, resulting phases are separated. The organic phase is treated with gaseous hydrochloric acid to crystallize anastrozole hydrochJoride. Crystalline salt of anastrozole hydrochloricle is further treated with sodium carbonate solution to get free base of anastrozole and crystallized in hydrophobia solvent such as cyclohexane to get purified anastrozole.
US patent, application 2006/0276657 discloses preparation of anastrozole by treating bromomethyl derivative of formula III with 1.2.4- triazole sodium in dimethylibrmamide and in presence of suitable base and resulting crude anastrozole is purified by selective extraction using mixture of solvents such as toluene, linear. branched or cyclic C5-8 hydrocarbon, water. N-methylpyrrolidine and C|.; alcohol mixed with water. Particularly the quenched reaction mixture is selectively extracted and re-extracted with toluene, heptane and water followed by washing of organic
layer with methanol and water. Thereafter heptane is added to organic la\er to precipitate anastrozole which is isolated by filtration. It is further recrystalli/ed in isopropyl alcohol and heptane to get pure anastrozole.
PCI publication WO 2005/105762 discloses the purification of crude anaslrozolc through anastrozole acid addition salt formation such as hydrochioridc. fumarate and oxalate. Specifically crude anastrozole is treated with corresponding acid in acetone to get anastrozole acid salt which is recrystallized from acetone. The purified anastrozole acid salt is neutralized to anastrozole by using base such as potassium hydroxide, bicarbonate or carbonate in water and the resulting anastrozole is further recrystallized using solvent such as ethyl acetate, hexane. heptane, toluene, aqueous solvents such as methanol. ethanol. isopropanol. acetonitrile. acetone-. tetrahydrofuran, dimethylfomiamidc. dioxanc or a combination thereof.
WO 2007/039913 publication discloses preparation of anastrozole wherein crude anastrozole is purified by column chromatography followed by recrystallization with a solvent preferably in ethyl acetate and hexane or acetone and water.
Recently a US patent application 2007/0100148 has published which discloses two processes for the purification of anastrozole. First process comprises crystallization of the anastrozole using isopropanol and water and in second process anastrozole is purified by column chromatography using ethylacctate as a cluting agent.
In view of the above, it has turned out that it is difficult to manufacture anasirozole in the required quality by following simple crystallization. The known processes comprise reaction of bromo derivative of formula 111 with 1.2.4 triazole or iis sail as described above have been found to give isoanastrozote isomer of formula VI in unacceptable amounts. This impurity along with other impurities is difficult to remove by usual working up procedures leading to extensive and expensiu-
purification processes. Most of the processes disclose the purification of anastrozole to remove unwanted iso anastrozole impurity of formula VI using column chromatography and crystallization or by selective extraction using large volumes of solvent. The use of column chromatography at commercial scale is tedious, cumbersome and time consuming, therefore there is an urgent need 10 dcxelop a simple and efficient process to purify anastro/olc which can be easily implemented on commercial scale.
It is an object of the present invention to devise a simple and commercially attractive process to remove isoiner impurity and prepare highly pure anastrozole.
SUMMARY OF HIE INVENTION
Accordingly, in one embodiment, the present invention provides a process to prepare highly pure anastrozole. comprising the steps of:
a) preparing a solution of crude anastrozole in a non polar solvent.
b) adding silica gel in to the solution.
c) stirring the reaction mixture for 30 to AOminutes,
d) filtering the solution.
e) concentrating the filtrate.
f) recrystalli/ing the residue in a suitable organic solvent or mixtures thereof.
g) optionally repeating steps a to f. h) and isolating pure anastrozole
In yet another embodiment, the present invention provides a process for preparing highly pure anastrozole comprising the steps of:
a) condensing 2.2'-(5-bromomethyl-l.?-phen\'lene)-di-(2-methyl propioniirile) of formula 111 with alkali metal salt of 1.2.4 triazole in a polar aprotic solvent at -5 to -10oC.
h) quenching the reaction mixture with demineralized water and stirred,,
c) isolating the crude anastrozole.
dy preparing a solution of crude anastro/ole in a non polar solvent.
c) adding silica gel in to the solution.
f) stirring the reaction mixture for 30 to 60minntes.
g) filtering the solution.
IV) concentrating the filtrate.
i) recrystallizing the residue in a suitable organic solvent or mixtures thereof.
j) optionally repeating steps d to i.
k) and isolating pure anastrozole.
DETAILED DESCRIPTION OF THE INVENTION
In one preferred embodiment, the present invention relates to a process lor purifving anastrozole wherein, the removal of isomeric products such as isoanastro/ole of formula VI and other impurities are minimized by treatment of crude anastro/ole using gel purification and optionally recrystallizing anastrozole in an organic solvent or mixtures thereof.
In one embodiment, the present invention provides a process for preparing highh pure anastrozole by treating crude anastrozole with silica gel in non polar solvent such as toluene, hexane. heptane, xylene or mixtures thereof and preferably toluene is used. The solution can be further stirred at 0 to 80°C and more preferably at 25 10 45°C to get clear solution. To this clear solution silica gel (100-200mesh) is added
and stirred for 5-120minutes at 25 to 45°C more preferably for 30-60miiuites at 30 to 35°C followed by removing the silica ge! by suitable technique such as filtration. Toluene is evaporated from the filtrate under vacuum to get solid residue, which is then heated in diisopropyl ether for 1-3hours preferably for 2hours and thereafter product is isolated by tllteration.
Optionally the resulting product is rccrystallized in suitable organic ^ohcnt or mixtures thereof to get highly pure anastrozole.
The organic solvent can be selected from alcohols such as ethanol. methanol. n-propanol. isopropanol. or mixtures thereof: ketones such as acetone, methvl isobutvl ketone. methylethylketone, or mixtures thereof : ethers such as diisoprop>l ether, isopropyl ether or mixtures thereof esters such as ethyl acetate: aliphatic or aromatic hydrocarbon solvents such as toluene, xylene or mixtures thereof or c\clic hydrocarbons such as cyclohexanc or halogenated solvents such as mcilnlene chloride or mixtures thereof or preferably the solvent is cthanol or cyclobexane and ethylacetate.
Anastrozole obtained by the described purification process may have a purity of at least 99.7% area by HPLC. more preferably, of at least 99.8%. and e\en more preferably, of at least 99.94% area by HPLC. Anastrazole obtained by the described purification process may contain at least one of the following impurities; not more than 0.15%. preferably not more than about 0.05% area by I1PLC of isoanastauole. not more than about 0.05% area by IIPI.C of ?,.2"-(5-methyl-l .3-phem lcnci-di-(2-methyl propionilrile) of formula II.
In yet another embodiment, the present invention provides a process for preparing highly pure anastrozole of formula 1 by condensing 2.2'-(5-bromomethyM.3-phenylene)-di-(2-methyl propionitrile) of formula III with alkali metal salt of 1.2.4-triazole in a polar aprotic solvent at 10 to -25"C. more preferabh' at 0 to -15"C and most preferabh at -5 to -10oC
The alkali metal salts of 1.2.4-triazole can be selected from 1.2.1- tria/ole sodium.
1.2.4- triazole potassium.and the like.
The polar aprotic solvent can be selected from temihydrofuran. acetone, acetomtrilc.
climethylformamide. dimethylsultbxide or mixtures thereof. More preferably the
solvent is dimethyltbrmamidc. dimcthylsulfovidc or mixtures thereof and most
preferably the solvent is climethylformamide.
Particularly, the condensation is carried out by suspending 1.2.4- triazole sodium in
dimethylfonnamiclc followed by addition of a solution of 2.?,'-(5-bromomethyl-1.3-
phenyleneHli-(2-methyl propionitrile) in dimethyltbrmamide. The resulting reaction
mixture is maintained at a temperature of 10 to -25°C for 2-3hrs hrs and more
preferably at -5 to -10°C for Ihr,
After completion of the reaction, the reaction mixture is quenched with demineralized water and finally stirred for 3-4 hrs at 1 0-1 5°C. preferably for 2-3hrs. I he progress of reaction is monitored by thin layer chromatography (I I.C) or b\ high pressure liquid chromatography (H'PLC). The amount of starting material should be less than n.5% \v/y by HPLC. 1 he precipitated crude anastrozole is isolated by filtration followed by washing with water.
The resulting anastrozole is analysed by high performance liquid chromatography and two major impurities along, with other unknown impurities have been detected in the analysis. The two major impurities are isoanastrozole of formula VI which is present in 1-10% area by IIPl.C and 2.2M>metny]-1.3-phcny]eneKli-(2-mcth>l
propionitrile) of formula 11 which is present in 0.3-10% area by 11 PI C. Hence, anastrozole is purified to remove these impurities along with some unknown impurities to get the desired purity of anastrozole which should comply with the regulatory aaencies.
Particularly, the crude anastrozole is dissolved in non polar solvent such as toluene. hexane. heptane, xylene or mixtures thereof and more preferably toluene is used. The solution can he further stirred at 0 to 8()°C and more preferably at 25 to 45"C to get clear solution. To this clear solution silica gel is added and reaction mixture is stirred for sufficient time so that impurities can get adsorbed on silica gel. Specifically the reaction mixture is stirred for 5-120minutcs at 25 to 45°C and more preferably for 30-60 minutes at 30 to 35 "C. Thereafter silica gel is removed by suitable technique such as filtration. 1 he solvent is evaporated under vacuum to get solid residue which !•-then heated in cliisopropyl ether for 1-3hours preferably for 2hours and thereafter product is isolated by filteration.
Optionally the resulting product is recrystallized in suitable organic solvent or mixtures thereof to get highly pure anastro/olc.
I he organic solvent can be selected from alcohols such as ethanol. mcthanol. n-propanol. isopropanol. or mixtures thereof : ketones such as acetone. methyl isobutyl ketone. methylethylketone. or mixtures thereof : ethers such as diisopropyl ether, isopropyl ether or mixtures thereof: esters such as ethyl acetate: aliphatic or aromatic hydrocarbon solvents such as toluene, xylene or mixtures thereof or c\clic hydrocarbons such as cyclohexane or halogenated solvents such as methylenc chloride or mixtures thereof or preferably the solvent is ethanol or cyclohexane and ethyl acetate.
I he silica gel used for purification can have particle size range from 6()-40()niesh. 240 400 mesh. 100-200 mesh, or 60-120 mesh etc. The ratio of crude anastrozole to silica gel can be 1:0.1 to 1:20. more preferably 1:0.4 to 1:3 and most preferabh the ratio of crude anastrozole to silica gel is about 1:0.5 to 1:1.
Anastrozole obtained by the described purification process may have a puritx of at least 99.7% area by HPLC. more preferabh'. of at least 99.8%. and even more preferably, of at least 99.94% area by HPLC. Anastrazole obtained by the described purification process may contain at least one of the following impurities: not more
than 0.15°o. preferably not more than about 0.05% area by HPLC of isoannstra/.oie. not more than about 0.05% area by HPLC of 2.2'-(5-methyl 1- 1.3-phen\ lene)-cli-(2-methyl propionitrile) of formula II.
In preferred embodiment of the present invention the treatment of crude anastro/ole with silica gel is not limited for single use but the crude product can be treated \\ith silica gel for more than once if the desired purity of the anastro/ole is not attained. Generally, the treatment of crude anastrozole with silica gel is repeated two times to gel the highly pure anastrozole.
Purity data as given above have proved that the use of silica gel for the purification of crude anastro/ole is very efficient to remove major impurity of anastro/ole i.e. isoanastrozole. Further, the process does not employ tedious column chromatograph\ to purify the crude anastrozole. The process is cost effective, industrially feasible, simple and easy to carry out and furthermore time consumption is less. 1 he process of the invention is illustrated by the following examples, \\hich is b\ way ol illustration only and not to be considered to limit the scope of the invention in any manner.
EXAMPLES
Example 1
Preparation of Anastro/ole
To a cooled suspension of 1.2.4- tria/ole sodium (1.5 g: 0.082-1 moles! in climeth) Ifonnamide (-10 ml), a solution of 2.2'-(5-bromometh\ l-1.3-phen\ !ene)-di-(2-methyl propionitrile) (10.0 g: 0.033 moles) in A'.A'-climethylformamide (25 ml) was added.. The reaction mixture was stirred at -5 to -10°C for 45 minutes then quenched with demineralized water (260 ml) and thereafter stirred for 2 hours at 10-15T. The precipitated product was filtered, washed with water and dried to gel the title compound. The HPLC purity was as follows:- anastrozole : 8^.35%; isoanastro/o e : 7.14%: 2.2"-(5-methyl-1.3-pheny1ene)-di-(2-metliy1 propionitrile) of formula 11 : 0.54%.
Example 2
Purification of Anastrozulc
To a clear solution of crude product (4.0 g) in toluene (30 ml), silica gel (100-200 mesh. 2.5 g) was added and stirred for 30 minutes. Thereafter silica gel was filtered of I and toluene was exaporatcd to get residue. The resulting residue was further taken in diisopropylether (100 ml) and re fluxed, thereafter stirred at 30-35"C lor 2 hours. The reaction mixture was tillered to get crystalline residue. The HPLC puriiy was as follows:- anastrozole : 93.44%: isoanastrozole : 4.28%: Compound of formula II : 0.50%. Yield: 2.0 g
To a clear solution of crystalline residue (2.0 g) in toluene (20 ml), silica gel (1 00-200 mesh. 1.0 g) was added, stirred for 30 minutes and filtered to remove silica gel. From the resulting filtrate toluene was evaporated to get solid residue. Solid residue \\as further dissolved in ethanol (3.6 ml) and stirred to get a clear solution. I he reaction mixture was cooled and filtered to get the crystalline anastrozole. The HPLC purity was as follows:- anastrozole : 99.93%: isoanastrozole : 0.02%: Compound of formula II : Not detected. Yield: 1.0 g
Example 3
Preparation of Anastrozole:
To a cooled suspension of L2.4-tria7,ole sodium (90.Og; 0.988 moles) in \.V dimetbylformamide (480 ml), a solution of 2.2 -(5-bromomctb\J-1.3-phcnylenc)-di-(2-methyl propionitrile) (120 g: 0.394 moles) in N.N-dimethylformamide (300ml) was added. The reaction mixture was stirred at -5 to -10"C for 45 minutes then quenched with demineralizecl water (3.1L) and stirred for 3 to I hours at 10-15'X'. The precipitated solid product, thus obtained, was filtered, washed \\ith water and dried to get the title compound (78g). The HPLC purity was as follows:- anastrozole : 83.28%: isoanastrozole : 1.85%: Compound of formula II : 7.8%.
Exam ple 4
Purification of Anastrozole
To a clear solution of crude anastrozole (78 g) obtained from example 3 in toluene(720 ml), silica gel (100-200 mesh. 36 g) was added and stirred lor 30 minutes. Siheagcl was filtered off and the filtrate was exaporated under reduecd pressure to get solid residue. The solid residue was re fluxed with diisoprop\l ether then reaction mixture was cooled down to 30-35"C and further stirred for 2.5 hours. The reaction mixture was filtered to get crystalline residue. The HPLC purity was as follows:- anastrozole : 96.56%: isoanastroxole : 1.2%; Compound of formula 11 : 0.06%. Yield: 56.Og.
To a clear solution of crystalline residue (56 g) in toluene (560 ml), silica gel (100-200 mesh. 1 7.0g) was added and the reaction mass was stirred tor 30 minutes Silica gel was filtered out and toluene was removed by evaporation under reduced pressure. The resulting residue was dissolved in ethanol (100 ml) and stirred to get clear solution, which was cooled to 0-5°C and filtered to get crystals of pure anastrozole. The HPLC purity was as follows:- anastrozole : 99.97%: isoanastrozole : 0.01%; Compound of formula 11 : Not detected. Yield: 27.0 g
Example 5
Preparation of Anastrozole:
To a cooled suspension of L2.4-tria7.olc sodium (88.5g: 0.972 moles) in N.N-dimcthylfoiTna.mi.de (472 ml), a solution of 2.2 -(5-bromomethy]-1.3-pheny lcnc)-di-(2-methyl propionitrile) (118 g: 0.387 moles) in N.N-dimelhylibrmamide (295ml) was added. The reaction mixture was stirred at -5 to -10"C for 45 minutes then quenched with demineralizecl water (3.0L) and stirred for 2 hours at 10-15"C. The precipitated solid product, thus obtained. \\as filtered, washed with uater and dried to get the title compound (74.4 g). The HPLC purity was as folkms:-anastrozole : 84.35%: isoanastrozole : 1.38%: Compound of formula II : 8.66%.
Example 6
Purification of Anastro/.ole
To a clear solution of crude anastrozole (74.4 g) obtained from example 5 in toluene (687ml) .silica gel (100-200 mesh. 34.3 g) was added and stirred for 30 minutes. Silicagcl was filtered off and the filtrate was evaporated under reduced pressure to get solid residue. Solid residue was further refluxcd with cliisoprop>] ether, thereafter cooled down to 30-35°C and stirred for 2.0 hours. The reaction mixture was liltercJ to get crystalline product. The HPLC purity was as follows:- anastrozole : 96.5%: isoanastro/ole : 1.2%: Compound of formula II : 0.06%. Yield: 45.Og. To a clear solution of crystalline product (45g) in toluene 1.450 ml), silica gel (100-200 mesh .13.5 g) was added and the reaction mass was stirred for 30 minutes. Silica gel was filtered off and toluene was removed by evaporation under reduced pressure. 1 he resulting residue was further dissolved in cthanol (80.0 ml) and stirred to get clear solution. The reaction mixture was cooled to 0-5"C and filtered to get pure anastrozole. The HPLC purity was as follows:- anastrozole : 99.86%: isoanastrozole : 0.02%: Compound of formula II : 0.01%. Yield: 25.5g.
Example 7
Preparation of Anastrozole:
To a cooled suspension of 1.2,4-triazole sodium (89.17g: 0.979 moles) in N'.\-diniethylformamide (298.0 ml), a solution of 2.2 -(5-bromomcthyl-l .3-phcmlcne)-di-(2-methyl propionitrile) (118.9 g: 0.389 moles) in N.N-dimcth\lformanmle (.">98ml) was added. 'The reaction mixture was stirred at -5 to -10"C for 45 minutes then quenched with demineralized water (3.ID and stirred for 2 hours at 10-15 X'. The precipitated solid product, thus obtained, was filtered, \\ashecl with \\ater and dried to get the title compound (83.3 g). The HPLC purity was as follows:-anastrozole : 79.34%; isoanastrozole : 4.7%: Compound of formula II : 6.78%.
Example 8
Purification of Anastrozole
To a clear solution of crude anastrozole (8.3.,3g) obtained from example 7 in toluene (714 ml), silica gel (100-200 mesh. 35.7 g) was added and stirred tor 30 minutes. Silicagcl \\as til tercel off and the .tlltratc was evaporated undo' reduced pressure to get solid residue. The solid residue was further refluxec! with cliisopropyl ether thereafter cooled down to 30-35"C and stirred for 2.0 hours. The reaction mixture was filtered to get crystalline product. The HPLC purity was as follows:- anastrozole : 88.62%: isoanastrozole : 4.39%: Compound of formula 11 : 0.75%. Yield: 39.23g. To a clear solution of crystalline product (39.23 g) in toluene (400 ml), silica gel (100-200 mesh .12.0g) was added and the reaction mass was stirred for .30 minutes. Silica gel was filtered out and toluene was removed by evaporation under reduced pressure. The resulting residue was further dissolved in cthanol (7?. ml) and stirred to get clear solution. The reaction mixture was cooled'to 0-5"C and filtered to get pure anastrozole. The HPLC purity was as follows:- anastrozole : 99.82%: isoanasiro/ole : 0.04 %: Compound of formula 11 : Not detected. Yield: 24.5g.
Example 9
Preparation of Anastrozole:
To a cooled suspension of 1.2.4-triazole sodium (15.9g; 0.175moles) in \'.\-dimethylformamide (53.0 nil), a solution of 2.2 -(5-bromomcthyl-] .3-phenylcneHli-(2-rnethyl propionitrile) (20 g: 0.065 moles) in N.N-dirnethylfonnamidc (50m!) was. added. The reaction mixture was stirred at -5 to -10"C for 45 minutes then quenched with demineralized water (520 ml) and stirred for 2 hours at 10-15"C. The precipitated solid product, thus obtained, was filtered, washed with water and dried to get the title compound (16.0g). The HPLC puriu was as follows:-anastrozole : 87.34%: isoanastrozole : 3.2.3%; Compound of formula II : 7.8.3%.
Example 10
Purification of Anastrozole
To a clear solution of crude anastrozole (16g) obtained from example 9 in toluene(60ml) .silica gel (100-200 mesh. 5.0 g) was added and stirred for 30 minutes. Silicagel was filtered off and the filtrate was evaporated under reduced pressure to get solid residue. The solid residue was further rcfluxcd with diisopropyl
ether thereafter cooled down to 30-35oC and stirred for 2.0 hours. The solution was tillered to get crystalline residue (7.0g).
To a clear solution of crystalline residue (7.0g) in toluene (40 ml ). silica uel i 100-200 mesh .2.0 g) was added and the reaction mass was stirred for 30 minmes. Silica gel was filtered out and toluene was removed by evaporation under reduced pressure. The resulting residue was further dissolved in ethylacetate (7.0 ml) at 4()-45"C and stirred to get clear solution. To this clear solution cyclohexane (14ml) was added at 40-45"C then cooled down to 20-25oC and further stirred for 2.0 hours. I he reaction mixture was further cooled to 5-10oC and stirred for 2.0 hours then tillered to get pure anastrozole. The HPLC purity was as follows:- anastrozole : 99.94%: isoanastrozole : 0.01%: Compound of formula II : Not detected. Yield :4.0g.
Example 11
Preparation of Anastrozole
To a cooled suspension of 1.2.4-tria7ole sodium (%96g: l.U5molcsi in \.V dimcthylformamide (512 ml), a solution of 2.2 ~(5-bromoincth\l-l .3-phem lenei-di-(2-inethyl propionitrile) (128 g: 0.42 moles) in N.N-dimethylformamide (320ml) was added. The reaction mixture was stirred at -5 to -10°C for 45 minutes then quenched with clemineralized water (3.3L) and stirred for 2 hours at 10-15°C. The precipitated solid product, thus obtained, was filtered, washed with water and dried to get the title compound (94,Og). The HPLC purity was as follovvs:-anastrozole : 89.06%: isoanastrozole : 1.99%: Compound of formula II : 7.78%.
Example 12
Purification of Anastrozole
To a clear solution of crude anastrozole (94.Og) obtained from example 1 1 in toluene (564ml). silica gel (100-200 mesh. 28.2 g) was added and stirred tor 30 minutes. Silicagel was filtered off and the filtrate was evaporated under reduced pressure to get solid residue. The solid residue was further refluxecl with, diisopropyl ether thereafter eooled down to 30-35°C and stirred for 2.0 hours. The solution was filtered to get crystalline residue (60.Og). The HPLC purity was as follows:- anastrozole : 98.06%: isoanastrozole : 1.33%: Compound of formula II : 0.56%.
To a clear solution of crystalline residue (60.0g) in toluene (600mlI silica gel (100-200 mesh . 18.0g) was added and the reaction mass was stirred for 30 minutes. Silica gel was filtered off and toluene was removed by evaporation under reduced pressure. The resulting residue is further dissolved in etlianol (120ml) and stirred lo get a clear solution. The solution was cooled down to 0 to
5°C and filtered to get crystalline anastrozole (36g). The HPLC purity was as follows:- anasirozole : 99.02%: isoanasltrozole : 0.44%: Compound of formula II : 0.24%. To a clear solution of crystalline anastrozole (36g) in toluene (360ml). silica gel (l00-200 mesh. 10.8g) was added and the reaction mass was stirred for 30 minutes. Silieagel was filtered off and the filtrate was evaporated under reduced pressure, The resulting residue is recrystallized in ethanol (72 ml) to get highly pure anastro/oie. The IIPI.C purity was as follows:- anastrozole : 99.76%: isoanastro/ole : 0.11%: Compound of formula 11 : Not detected. Yield: 23.4g,

WE CLAIM
1. A process to prepare highly pure anastrozole of formula I.
(Formula Removed)
comprising the steps of:
a) preparing a solution of crude anastrozole in a non polar sohent. h) adding silica gel in to the solution.
c) stirring the reaction mixture for 5 to 120 minutes.
d) filtering the solution.
e) concentrating the filtrate.
f) recrystallizmg the residue in a suitable organic sohent or mixtures thereof.
g) optionally repealing steps a to f. h) and isolating: pure anastrozole.
2. The process according to claim 1. wherein step a), non polar solvent is selected from toluene, hexane. heptane, xylene or mixtures thereof
3. The process according to claim 1. wherein step h). siliea gel is used in ratio ot" 1:0.1 to 1:20. more preferably 1:0.4 to 1:2, and most preferably 1:0.5 to 1:1.
4. The process according to claim 1. wherein step f). suitable organic solvent is selected from alcohols such as ethanol. methanol. n-propanol. isopropanol. or
mixtures thereof : ketones such as acetone, methyl isohutyl ketone. methylethylketone. or mixtures thereof : ethers such as diisopropyl ether. isopropyl ether or mixtures thereof: esters such as ethyl acetate: aliphatic or aromatic hydrocarbon solvents such as toluene, xylene or mixtures thereof or cyclic hydrocarbons such, as cyclohcxane or halogenated solvents such as mcthylene chloride or mixtures thereof or preferably the solvent is etrumol or cyclohexane and ethyl acetate.
5. A process for preparing highly pure anastrozole comprising the steps of:
a) condensing 2,2'-(5-bromomethyl-1.3-phenylene)-di-(2-methyl propionitrile) of formula III with alkali metal salt of 1.2.4 triazole in a polar aprotic solvent at -25 to 10°C.
b) quenching the reaction mixture with demineralized water and stirred.
c) isolating the crude anastro?olc.
d) preparing a solution of crude anastro/.ole in a non polar solvent.
e) adding silica gel in to the solution.
f) stirring the reaction mixture for 20 to 120minutes.
g) tillering the solution.
h) concentrating the filtrate.
i) recrystallizing the residue in a suitable organic solvent or mixtures thereof.
i) optionally repeating steps d to i.
k) and isolating pure anastrozole.
6. The process according to claim 5. wherein step a), polar aprotic solvent is selected
from tetrahydrofuran. acetone. acetonitrile. dimethylformamide. dimethylsulfoxide or mixtures thereof. More preferably the solvent is dimethylforamicle. dimethylsulfoxide or mixtures thereof and most preterably the solvent is dimethvlfonnainicle.

7. The process according to claim 5. wherein step d). non polar solvent is selected from toluene, hexane. heptane, xylene or mixtures thereof.
8. The process according to claim 5. wherein step e). silica gel is used in ratio of 1 :0.1 to 1 :20, more preferably 1:0.4 to 1:2 and most preferably 1:0.5 to 1:1.
9. The process according to claim 5. wherein step f). the stirring is preferabiv earned out for 30-60 minutes.
10. The process according to claim 5. wherein step i). suitable organic solvent is selected from alcohols such as ethanol. methanol. n-propanol. isopropanol. or mixtures thereof iketones such as acetone, metlnl isobuul ketone. mcthylethx Iketone. or mixtures thereof : ethers such as diisopropyl ether, isopropyl ether or mixtures thereof; esters such as ethyl acetate: aliphatic or aromatic hydrocarbon solvents such as toluene, xylene or mixtures thereof or cyclic hydrocarbons such as cyclohexane or halogenatecl solvents such as methylene chloride or mixtures thereof or preferably the solvent is ethanol or cyclohexane and ethyl acetate.