FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of high purity anastrozole. Anastrozole which is (2,2'-[5-(lH-l,2,4-triazol-l-ylmethyI)-l,3-phenylene] dJ(2-methylpropio-nitri]e) has the formula-I

The invention also relates to an improved process for the preparation of or its acid addition salts of anastrozole.
Anastrozole is an aromatase inhibitor useful for the treatment of breast cancer
BACKGROUND OF THE INVENTION
Anastrozole is reported for the first time by Imperial Chemical Industries in EP 296749 (equivalent US pat. 4935437). Pharmacology and pharmacokinetics of anastrozole is reviewed in Breast Cancer Res. Treat. 30, 103-Ul (1994) and J. Steroid Biochem. Moke. Biol 53, 175-179, (1995). Clinical trial of anastrozole in advanced breast cancer is published in Cancer. 79, 730 (1997).
Two processes are described in EP 296749 for the preparation of anastrozole. The first process consists of conversion of 3,5-(bisbromomethyl)toluene of the formula-II to the corresponding nitrile of the formula-Ill by treatment with potassium cyanide (Scheme-I).
The nitrile compoimd of the formula-Ill is reacted with sodium hydride and methyl iodide to get the corresponding tetramethyl derivative of the formula-IV. Compound of the formula'IV is reacted with N-bromosuccinimide to get the romomethyl derivative of

the formula-V, which on treatment with sodium 1,2,4-triazole gave the crude anastrozole of the formula-h Crude anastrozole was purified by column chromatography and crystallization from cyclohexane/ethyl acetate to get the purified material with a melting point of 81-82°C. Neither the yield nor the HPLC purity of this material is mentioned in

Attempts to make anastrozole by the above-mentioned process gave poor yield (<50%) and poor quality (< 90% by HPLC) material. Attempts to purify anastrozole by the given crystallization procedure was found to be not successful in reducing the level of isomeric impurity of the formula-VI to less than 0.1%. The isomeric impurity of the formula-VI present in anastrozole after crystallization from ethyl acetate/cyclohexane was found to be more than l.0%i by HPLC. Therefore the process is not viable for commercial production of anastrozole with the pharmaceutically acceptable purity.
In the second process methyl 3,5-dimethylbenzoate is reacted with NBS to get methyl 3,5-bis(bromomelhyl)benzoate of the formula-VIl (Scheme-II). The bromo derivative of the formula-Vn is reacted with potassium cyanide to get the corresponding nitrile derivative of the formula-VIIL Methylation with methyl iodide followed by reduction of the ester group present in compound of the formula-IX with lithium borohydride gave the compound of the formula-X. Conversion of the hydroxy group present in compound of

the formula-X to the chloro derivative using thionyl chloride followed by reaction with 1,2,4-triazole gave the required anastrozole along with the isomer derivative of the formuIa-VI. The required anastrozole was separated from the isomeric impurity by column chromatography.

The main disadvantage in this process is the formation of isomeric impurity. As the removal of this impurity requires column chromatograph, which is not a convenient operation on production scale this process is not commercially viable.

DESCRIPTION OF THE INVENTION
Keeping in view of the difficulties in commercialization of the above process mainly with respect to yield and quality of anastrozole we aimed to develop a simple purification process, which will enhance the purity without losing much of the anastrozole while
purification.
Anastrozole has been picking up fast as a remedy for treatment of breast cancer. Keeping in view of the difficulties in commercialization of the above-mentioned processes for the preparation of anastrozole, we aimed to develop a simple and economical process for commercial production of anastrozole.
We observed that a promising approach for such a process is to (a) improve the process to avoid/reduce the formation of isomeric impurities (b) improve the quality of anastrozole without losing much of it during the purification (c) avoid the usage of costly and uncommon column chromatography technique to purify anastrozole as such process would produce a lot of solvent waste.
Accordingly, the main objective of the present invention is to provide an improved process for the preparation of anastrozole of the formula-I which avoids/reduces the formation of impurities.
Still another objective of the present invention is to provide an improved process for the preparation of anastrozole of formula-I, which avoids the usage of column chromatography.
Another objective of the present invention is to provide a process for the preparation of >99.8% purity anastrozole of formula-I with all the impurities below 0,1% level.
The present invention has been developed based on our finding that the isomeric impurity of formula-VI cannot be removed to <0.1% level by following the patent process or by any other crystallization techniques. The level of this impurity in anastrozole is always

>0.5% even after repeated crystallization. Surprisingly, this impurity can be reduced to below 0.1% level by purification of anasrozole acid addition salts. After removal of this impurity neutralization of the acid addition salt gives pure anastrozole of formula-I with more than 99.8% purity and all the impurities below 0.1% level. Purification of anastrozole to >99.8% via formation of acid addition salts is novel and applied for the first time in making high purity anastrozole.
During process development of anastrozole on commercial scale we observed that with increasing batch size isomer content in crude product increased (from 0.8-1.0% on less than 100 g scale to 3-5% on more than kilogram scale). Introduction of a non-polar solvent in this coupling reaction along with DMF reduced the level of isomeric impurity formation during scale up operations. The nonpolar solvents selected for this reaction include aromatic solvent such as toluene, xylenes, hydrocarbon solvents such as hexane, heptane, cyclohexane, etc.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of anastrozole of the formula-I,



(ii) reacting the bromo compound of the formula-V, with sodium/potassium triazole
in DMF with or without a non-polar solvent (iii) quenching the reaction mass into water medium and extracting the crude
anastrozole formed into an organic solvent (iv) distilling the organic solvent and treating with organic or mineral acid to form the
acid addition salt, (v) recrystallizing the acid addition salt and neutralizing the salt with a base to
liberate the anastrozole and (vi) crystallizing the anastrozole from an organic solvent to get pharmaceutically
acceptable grade product.
The non-polar solvent used in step (i) is selected from halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, hydrocarbon solvents such as benzene, cyclohexane, heptane, preferably cyclohexane, or chloroform. The brominating agent used in step (i) is selected from N-bromosuccinimide, l,3-dibromo-5,5-dimethylhydentoin, etc., preferably N-bromosuccinimide. The non-polar solvent used in step (ii) is selected from hexane, heptane, toluene, cyclohexane, xylenes, preferably toluene or cyclohexane. The organic solvent used for extraction of crude anastrozole in step (iii) is selected from esters like ethyl acetate, halogenated solvents like methylene chloride, ethers like diethyl ether, diisopropyl ether, hydrocarbon solvents like toluene, cyclohexane. The acids used in step (iv) are selected from organic acids such benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, benzoic acid, maleic acid, fumaric acid, succinic acid; mineral acids such as hydrocholirc acid, hyrobromic acid.

sulfuric acid, phosphoric acid. The treatment with acid may be carried out in the presence of in a polar solvent, which may be selected from methanol, ethanol, isopropanol acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, and water. The same solvents can be used for recrystallization of the acid addition salt of anastrozole also.
The base used in neutralization step (v) is selected from sodium or potassium hydroxide, bicarbonate or carbonates, amines like ammonia, alkylamines, etc. The solvents used for crystallization of anastrozole are selected from ethyl acetate, hexane, heptane, toluene, aqueous solvents such as methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dioxane or a combination thereof
The details of the invention are given in the Examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the present invention.
Example 1
Preparation of pure anastrozole of the formula-1
(i) Preparation of a, a, a\ a-tetramethyl-5-bromomethyl-l, 3-benzenediacetonitrile
of formula-V
Into a SOL glass flask was charged 12L of chloroform and 1.0kg of 5, a, a, a', a'-pentamethyi-1, S-benzenediacetonitrile of formula-IV. The reaction mass was heated to reflux temperature and charged 0.8kg of N-bromosuccinimide and lOg of m-chlorobenzoylperoxide. The reaction mass was maintained at reflux temperature for 3 hr. HPLC of the reaction mass indicated 90% of conversion. The reaction mass was cooled to 25 °C and charged 7L of water. The reaction mass was stirred for 30min and separated the water layer. Organic layer was washed with water (2 x 7L). Activated carbon (0.2Kg) and sodium sulfate (0.5Kg) were added to the organic layer and filtered Chloroform was distilled of from the filtrate to get 1.4kg of crude compound of formula-V. Purity by HPLC was >85%.

(ii) Preparation of crude anastrozole of formula-]
Into a lOL, three-necked RB flask was charged 1.4kg of above crude compound of formula-V and 7L of anhydrous DMF. The reaction mass was stirred for 30min and added 0.65kg of solid sodium triazole (prepared by reaction of molar quantities of 1,2,4-IH-triazole and sodium hydroxide in isopropanol at reflux temperature and isolated by filtering of the reaction mass at room temperature) in lots keeping the temperature below 25 °C. The reaction mass was maintained under stirring at this temperature for 4hr. HPLC of the reaction mass indicated the absence of starting material. The reaction mass was transferred into a 50L flask containing 21L of water and stirred for 30min. Reaction mass was extracted with toluene (2 x 3L and 1 x IL). Toluene layers were combined and washed with water (2 x 2L). Toluene was distilled of from the filtrate under vaccum to get 1.2kg of crude anastrozole.
(iii) Preparation of anastrozole p-toluenesulfonate salt
Acetone (5L) was added to the above step (ii) residue at room temperature and stirred for 30min to get a clear solution. p-Toluenesulfonic acid monohydrate (0.8kg) was added to the reaction mass and stirred for Ihr. Acetone was distilled of from the reaction mass and added 5L of acetone. The reaction mass was stirred at 25 °C for 12hr. Filtered the solids and washed the wet cake with IL of acetone. Wet weight is 1.50kg. The wet salt thus obtained is taken into a lOL three-necked RB flask and added acetone (5L). The reaction mass was heated to reflux temperature and maintained for Ihr. The reaction mass was cooled to 25° 0 and maintained for 3hr. The solids were filtered of and washed with acetone. The salt was dried at 50°C. Yield is 1.3kg. M. P. is 175.3°C. Purity by HPLC is 99.7%. Isomeric impurity is 0.04%. IR (KBr): 3426, 3106, 3051, 2988, 2235, 1605, 1551, 1534, 1496, 1463, 1441, 1406, 1372, 1296, 1267, 1221, 1192, 1165, 1121, 1031, 1009, 932, 912, 868, 817, 760, 704, 685, 644, and 565cm-'.
(iv) Preparation of pure anastrozole of the formula-I
Water (5L) and the above p-toluenesulfonate salt of anastrozole (1.2kg) were taken into a lOL, three-necked RB flask and stirred for 30min. pH of the reaction mass was adjusted to 8.5-9.0 with aqueous ammonia. Toluene (2L) was added to the reaction mass and

stirred for 30min. Toluene layer was separated and the aqueous layer extracted with 2 x 2L of toluene. Combined toluene layer was washed with 2L of water. Toluene layer was dried with sodium sulfate and distilled imder vaccum. Ethyl acetate (IL) and cyclohexane (4L) were added to the residue and heated to reflux temperature. The reaction mass was cooled to 10 °C and maintained for 2hr before filtration. Yield of pure anastrozole is 0.7kg. Melting point is 86.3''C. Purity by HPLC is 99.6%. Isomeric impurity is 0.06%. IR (KBr): 3102, 2985, 2950, 2236, 1606, 1502, 1476, 1454, 1428, 1389, 1359, 1273, 1220, 1205, 1138, 1013, 956, 895, 876, 763, 713, 680, and 664cm-'. 'H-NMR (3Q0MHZ, CDCb): 8.16 (s, IH, -NCHN-); 8.01 (s IH, -NCHN-); 7.34-7.54 (m, 3H, aromatic-H); 5.40 (s, 2H, ArCHi-); 1.73 (s, 12H, 4 x -CH3). '° C-NMR (75MHz, CDCI3): 152.07 (NCHN); 143.04 (NCHN); 136.44 (C-5); 123.99 {C-4 and C-6); 123.50 {C-2); 121.79(CN); 52.71(ArCH2); 36.99 {-CCH2); 28.76 (-CH3). Mass (EI-MS): 294 ([M + 1]° ); 293 ([Mf); 292 ([M-1]° ); 278 ([M - CH3]); 266 ([M + l]"" - ON); 225 ([Mf -triazole); 224 ([M - 1]° - triazole); 210 ([M + 1]° - CH:-triazole); 209 ([M1+ - [-CH2-triazole]).
Example 2
Preparation of pure anastrozole of the formula-I
(i) Preparation of a, a, a', a'-tetramethyl-S-bromomethyl-l, 3-benzenediacetonitrile
of formuIa-V
Into a 2L, three-necked RB flask was charged IL of carbon tetrachloride and lOOgof 5,a, a, a', a'-pentamethyl-l, 3-benzenediacetonitrile of formula-IV. The reaction mass was heated to reflux temperature and charged 80g of N-bromosuccinimide and Ig of m-chlorobenzoylperoxide. The reaction mass was maintained at reflux temperature for 10 hr. HPLC of the reaction mass indicated >90% of conversion. The reaction mass was cooled to 25 °C and filtered the insoluble succinamide. Solvent was distilled of from the filtrate to get 140g of crude compound of formula-V. Purity by HPLC was >85%.
(ii) Preparation of crude anastrozole
Into a IL, three-necked RB flask was charged 60g of sodiiun triazole monohydrate (prepared by reaction of molar quantities of 1,2,4-lH-triazole and sodium hydroxide in

isopropanol at reflux temperature and isolated by filtering of the reaction mass at room temperature) and 200ml of dry DMF under nitrogen atmosphere. The reaction mass was cooled to 20 °C. A solution of the above bromo compound of forraula-V (140g) in toluene {200ml) was added to the reaction mass over a period of 2hr. The reaction mass was maintained at this temperature until the completion of reaction. The reaction mass was transferred into 3L flask containing 1.5L of water and stirred for 30min. Reaction mass was extracted with toluene (2 x 300ml and 1 x 100ml). Toluene layers were combined and washed with water (2 x 200ml). Toluene layer was treated with activated carbon (5g) and filtered. Toluene was distilled of from the filtrate under vaccum to get I30g of crude anastrozole.
(iii) Preparation of anastrozole hydrochloride salt
The above prepared crude anastrozole (130g) was dissolved in acetone (500ml) and treated with isopropanol-HCl. The resulting solution was kept under stirring for
overnight. The reaction mass was cooled to 5-10°C and filtered. The wet cake was
washed with chilled acetone to get lOOg of anastrozole hydrochloride sah. HPLC purity is 99.3%. Isomeric impurity is 0.13%.
(iv) Recrystallization of anastrozole hydrochloride salt
The above prepared anastrozole hydrochloride (lOOg) was recrystallized from acetone to get pure anastrozole hydrochloride salt. HPLC purity is 99.3%. Isomeric impurity is
0.13%. M. P. is lOT° C. IR (KBr); 3519, 1452, 3142, 3126, 3027, 2988, 2883, 2739, 2647, 2559, 2232, 1610, 1562, 1532, 1470, 1440, 1389, 1378, 1264, 1222, 1194, 1142, 1106,1002, 950, 871, 762, 704, 664, 645, and 629cm''.
(v) Preparation of pure anastrozole of the formula-I
The above recrystallized anastrozole hydrochloride salt (75g} was dissolved in water and neutralized with sodium bicarbonate. The liberated base was extracted into toluene and the solvent distilled of under vaccum to get 63g of pure anastrozole. Purity by HPLC is 99.5%. Isomeric impurity is 0.07%.

Example 3
Preparation of pure anastrozole of the formula-l
(i) Preparation of crude anastrozole
Into a IL, three-necked RB flask was charged 45g of anhydrous sodium triazole and 250ml of dry DMF under nitrogen atmosphere. The reaction mass was cooled to 25 °C. Bromo compound of formuIa-V (JOOg, prepared according to the process given in EP 0296749, example 1) was added to the reaction mass over a period of 2hr. The reaction mass was maintained at this temperature until the completion of reaction. The reaction mass was transferred into 3L flask containing 1.6L of water and stirred for 30min. Reaction mass was extracted with toluene (2 x 300ml and 1 x 100ml). Toluene layers were combined and washed with water (2 x 200ml), Toluene layer was treated with activated carbon (5g) and filtered. Toluene was distilled of from the filtrate under vaccum to get 95g of crude anastrozole.
(ii) Preparation of anastrozole fumarate salt
The above prepared crude anastrozole (95g) was dissolved in acetone and added fumaric acid. The reaction mass was heated to reflux temperature and maintained for Ihr. The reaction mass was cooled to room temperature and maintained for 4hr. The solids were filtered and washed with isopropanol to get I20g.
(Hi) Recrystallization of anastrozole fumarate salt
The above prepared anastrozole fumarate was recrystallized from isopropanol to get pure anastrozole fumarate salt. HPLC purity is 99.3%). Isomeric impurity is 0.10%). M. P. is 102 °C. IR (KBr): 3130, 3068, 2991, 2943, 2232, 1688. 1607, 1522, 1469, 1439, 1394, 1376, 1348, 1279, 1222, 1182, 1133, 1013, 925, 879, 869, 783, 770, 703, 673, 648, and 558cm"'.
(iv) Preparation of pure anastrozole of the formula-I
The above recrystallized anastrozole fumarate salt was suspended in water and neutralized with ammonia. The liberated base was extracted into toluene and the solvent

distilled of under vaccum to get quantitative yield of pure anastrozole. Purity by HPLC is 99.6%. Isomeric impurity is 0.08%.
Example 4
Preparation of pure anastrozole of the formula-I
(i) Preparation of crude anastrozole
Into a 1L, three-necked RB flask was charged 60g of sodium triazole monohydrate and 400ml of dry DMF under nitrogen atmosphere. The reaction mass was cooled to 25 °C. Bromo compound of formula-V (lOOg, prepared according to the process given in EP 0296749, example 1) was added to the reaction mass over a period of 2hr. The reaction mass was maintained at this temperature until the completion of reaction. The reaction mass was transferred into 3L flask containing 1.6L of water and stirred for 30min. Reaction mass was extracted with toluene (2 x 300ml and 1 x lOOml). Toluene layers were combined and washed with water (2 x 200ml). Toluene layer was treated with activated carbon (5g) and filtered. Toluene was distilled of from the filtrate under vaccum to get 96g of crude anastrozole.
(ii) Preparation of anastrozole oxalate
The above prepared crude anastrozole (95g) was dissolved in isopropanol and added molar quantity of oxalic acid dihydrate. The reaction mass was stirred and maintained at room temperature for 4hr. The solids were filtered and washed with isopropanol to get 120g of crude anastrozole oxalate salt.
(iii) Recrystallization of anastrozole oxalate
The above-prepared crude anastrozole oxalate was recrystallized from isopropanol to get pure anastrozole oxalate saU. HPLC purity is 99.3%. Isomeric impurity is 0.10%, M. P. is
174°C. IR (KBr): 3143, 3098, 2986, 2930, 2581, 2232, 1890, 1719, 1699, 1614, 1566, 1543,1448, 1400,1369, 1283, 1196, 1116, 1007, 929, 903, 877, 759, 704, 665, 638, and 625cm-'.

(iv) Preparation of pure anastrozole of the formula-I
The above recrystallized anastrozole oxalate salt was suspended in water and neutralized with ammonia. The liberated base was extracted into ethyl acetate and the solvent distilled of under vaccum to get quantitative yield of pure anastrozole. Purity by HPLC is 99.6%. Isomeric impurity is 0.08%.
Advantages of present invention:
1. The process of the present invention avoids the usage of column chromatography while isolating anastrozole thereby making the process simple and economical
2. The process of present invention uses the solubility properties of acid addition salts in making the high purity (>99.8%) anastrozole with all impurities below 0.1% level.
3. The process of present invention produces anastrozole in high yield (>80%).
4. The process of present invention is applicable for commercial scale production.

(ii) reacting the bromo compound of the formula-V, with sodium/potassium triazole
in DMF with or without a non-polar solvent (iii) quenching the reaction mass into water medium and extracting the crude
anastrozole formed into an organic solvent (iv) distilling the organic solvent and treating with or mineral acid to form the
acid addition salt

(v) recrystallizing the acid addition salt and neutra'irjng the salt with a base to
liberate the anastrozole and (vi) crystallizing the anastrozole from an organic soivent to get pharmaceuticaliy
acceptable grade product,
2. A process as claimed in claim 1 wherein the non-po!ai- solvent used in step (i) is selected from halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, hydrocarbon solvents such as benzene, cyclohexane, heptane, preferably cyclohexane, or chloroform.
3. A process as claimed in claims 1 & 2 wherein the brominating agent used in step {i} is selected from N-bromosuccinimide, ] .3-dibromo-5,5-dimeihylhydentoin, etc., preferably N-bromosuccinimide.
4. A process as claimed in claims 1-3 wherein the non-polar solvent used in step (ii) is selected from hexane, heptane, toluene, cyclohexane, xylenes, preferably toluene or cyclohexane.
5. A process as claimed in claims 1-4 wherein the organic solvent used for extraction of crude anastrozole in step (iii) is selected from esters like ethyl acetate, halogenated solvents like methylene cloride, ethers like diethyl ether, diisopropyl ether, hydrocarbon solvents like toluene, cyclohexane.
6. A process as claimed in claims 1-5 wherein the acids used in step (iv) are selected from organic acids such as benzenesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, oxalic acid, benzoic acid; mineral acids such as hydrochloric acid, hyrobromic acid, sulfuric acid, phosphoric acid.
7. A process as claimed in claims 1-6 wherein the solvents selected for salt formation of anastrozole and its recrystallization are selected from methanol, ethanol, isopropanol acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, water or a mixture thereof

8. A process as claimed in claim 1-7 wherein the base used in neutralization step (v) is
selected from sodium or potassium hydroxide, bicarbonate or carbonates, amines [ike
ammonia or alkylamines.
9. A process as claimed in claim 1-8 wherein the solvents used for crystallization of
purified (>99%) anastrozole are selected from ethyl acetate, hexane, heptane, toluene,
aqueous solvents such as methanol, ethanol, isopropanol, acetonitrile, acetone,
tetrahydrofuran, dimethylforniamide, dioxane or a combination thereof.
10. A process for the preparation of high purity {>99.6%) anastrozole is substantially as
described in examples.