Description:FIELD OF THE INVENTION
[1] The present invention generally relates to an improved process for the preparation of an anticancer drug. More particularly, the present invention relates to an improved process for the preparation of an anti-estrogenic anticancer drug. Specifically, the present invention relates to an improved process for the preparation of Anastrozole. The present invention also discloses improved processes for the preparation of intermediates.

BACKGROUND OF THE INVENTION
[2] Anastrozole is orally administrable anti-estrogenic drug which belongs to aromatase-inhibiting family of medications. Anastrozole produces its anti-estrogenic effect by blocking the production of estrogen in the body. It is used along with other treatments for treating breast cancer. Anastrozole is specifically used for hormone receptor-positive breast cancer. It is also used in preventive therapies.
[3] The method for the preparation of Anastrozole starting from 1,3,5-trimethylbenzene was found in the literature (J. Org. Chem., 2272, 1967). Anastrozole is reported for the first time by Imperial Chemical Industries in EP 296749 (equivalent US patent No. 4,935,437). Pharmacology and pharmacokinetics of anastrozole is reviewed in Breast Cancer Res. Treat. 30, 103-111 (1994) and J. Steroid Biochem. Molec. Biol. 53, 175-179, (1995). Clinical trial of anastrozole in advanced breast cancer is published in Cancer, 79, 730 (1997).
[4] U.S. Pat. No. 4,935,437, discloses a process for preparing Anastrozole. In general, the process includes reacting 3,5-bis(bromomethyl)toluene with potassium cyanide to produce 3,5-bis(cyanomethyl)toluene, which is then reacted with methyl iodide to provide 3,5-bis(l-cyano-l-methylethyl)toluene intermediate. Next, this intermediate is reacted with N-bromosuccinimide followed by a reaction with sodium 1,2,4-triazole to produce anastrozole and its isomer, 2,2'-[5-(l,2,4-triazol-4-ylm-ethyl)-l,3-phenylene]di(2-methylpropionitrile) of formula (II).

[5] Since, the isomer of formula (II) is an undesired product; thus, there is requirement of an additional steps to isolate the desired isomer of Anastrozole from the mixture of both desired and undesired isomers.
[6] EP296749, discloses two processes for purification of Anastrozole. In first process 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 the purified product is reported. Further, this process resulted in poor yield (<50%) and poor quality (< 90% by HPLC) of product. Attempts to purify Anastrozole using crystallization procedure was found to be not successful in reducing the level of isomeric impurity to less than 0.1%. The isomeric impurity present in Anastrozole after crystallization from ethyl acetate/cyclohexane was found to be more than 1.0% by HPLC. Therefore, the process is not viable for commercial production of Anastrozole having pharmaceutically acceptable purity.
[7] In the second process there is formation of isomeric impurity and the removal of this impurity requires column chromatography, which is not a convenient operation on production scale this process is not commercially viable. It is important to mention that in both the processes neither yield nor purity of the product is reported.
[8] Since, the Anastrozole synthesized from the process described in U.S. Pat. No. 4,935,437 contains undesired isomeric form of Anastrozole; thus requiring additional steps to separate it from Anastrozole; which is a costly affair and not suitable for manufacturing at industrial scale. Therefore, which is there urgent need to invent an improved process for preparation of Anastrozole substantially free from undesired isomers or impurities.
[9] US patent application 2006/0035950 provides novel processes for purification of Anastrozole, avoiding the use of liquid chromatography. They 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 Anastrozole is purified via Anastrozole acid addition salt such as hydrochloride or hydrobromide 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 Hydrochloride. Crystalline salt of Anastrozole Hydrochloride is further treated with sodium carbonate solution to get free base of Anastrozole and crystallized in hydrophobic solvent such as cyclohexane to get purified anastrozole.

[10] US patent application 2006/0276657 discloses preparation of Anastrozole by treating bromomethyl compound of formula III with 1,2,4- triazole sodium in dimethylformamide 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, methylpyrrolidine and 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 layer to precipitate Anastrozole which is isolated by filtration. It is further recrystallized in isopropyl alcohol and heptane to get pure Anastrozole.
[11] Improved and commercially viable processes for the preparation of high purity Anastrozole by purification of Anastrozole via its isolated salt form are disclosed in WO 2005/105762 and US 20060035950. As compared to the processes described in EP 296749, the improved process also has the advantage of avoiding the usage of hazardous reagents, such as carbon tetra-chloride and benzoyl peroxide.
[12] A novel process for the preparation of Anastrozole is disclosed in WO 2006/000836. The new process comprises two or more of the steps for preparing Anastrozole from 3,5-Bis(2-cyanoisopropyl) toluene and novel intermediates.
[13] WO 2006/108155 discloses an alternative process for preparation and purification of Anastrozole. The new method for purification of the Anastrozole by selective extraction does not require the isolation of Anastrozole in the form of a salt, thus, the steps of transforming Anastrozole to its salt and then back to the free base, and the usage of toxic solvents, such as tetrachloride, are avoided. Hence, this improved process can be adapted easily and efficiently to industrial scale. However, the reaction condition of Anastrozole synthesis from 3,5-bis(2-cyanoisopropyl)benzylbromide is limited to the temperature below 0 °C, which is not a convenient operation. The long reaction time and the complicated steps, such as more than one temperature condition in one step, are also disadvantageous with respect to industrial application. Moreover, this method was found to be not successful in reducing the level of isomeric impurity of Anastrozole to 0.1%.
[14] WO 2005/105762 A1 discloses the preparation of anastrozole wherein 1-bromomethyl-3,5-bis(2-cyanoisopropyl)toluene is reacted with the sodium salt of 1,2,4-triazole. Thereby it was found that the isomer (2,2'-(5-((1 H-1,3,5-triazol-1-yl)methyl)-1,3-phenylene) bis(2-methyl-propanenitrile), also called isoanastrozole, is formed as an undesired by-product. Said isoanastrozole was present in anastrozole even after repeated purification by crystallization in an amount of more than 0.5% determined by HPLC. Furthermore, it was found that the content of isoanastrozole impurity can be significantly reduced to below 0.1% level by purification in form of Anastrozole acid addition salts, however, overall yield was quite low.
[15] In Ge, Zemei; Cui, Jialing; Cheng, Tieming; Li, Runtao; Chinese Journal of Medicinal Chemistry, (2003) Vol. 13, No. 3, 146-147, preparation of Anastrozole via N-alkylation of 1,2,4-triazole with 1-bromomethyl-3,5-bis(2-cyanoisopropyl)toluene by phase transfer catalysis is reported, wherein xylene is used as the solvent, K2CO3/KOH is used as the base, and tetra-n-butylammonium bromide (TBAB) is used as the phase transfer catalyst, and reaction was carried out under reflux conditions. However, this phase transfer catalysis requires harsh reaction conditions in view of reaction temperature and reaction time. The product was purified by repeated recrystallisations, however there is no information concerning purity detected by HPLC.
[16] WO 2006/108155 A1 describes a process for preparing Anastrozole via N-alkylation of 1,2,4-triazole with 1-bromomethyl-3,5-bis(2-cyanoisopropyl)toluene in the presence of a base selected from the group consisting of NaOH, KOH, K2CO3 and Na2CO3 at temperatures below -20°C. The resulting crude product is purified by aqueous extraction operations, filtration and recrystallisation, wherein the impurity profile of anastrozole is not more than about 0.16% area by HPLC of isoanastrozole, not more than about 0.14% area by HPLC of 3,5-bis(2-cyanoisopropyl)toluene, and not more than about 0.18% area by HPLC of other impurities.
[17] WO 2007/002722 A1 also discloses a process for preparing Anastrozole via N-alkylation of 1,2,4-triazole with 1-bromomethyl-3,5-bis(2-cyanoisopropyl)toluene in the presence of NaOH at temperatures below -20°C, wherein the product has a purity of 99.94% area by HPLC and 0.06% area by HPLC of an impurity other than isoanastrozole. The low reaction temperature of the processes of WO 2006/108155 A1 and WO 2007/002722 A1 are disadvantageous for industrial application.
[18] WO 2007/039913 discloses a process for preparing Anastrozole wherein 1-halogenomethyl-3,5-bis(2-cyanoisopropyl)toluene is reacted with the potassium or sodium salt of 1,2,4-triazole. The purity of the product is 99.9% area by HPLC after purification comprising aqueous work up operations, column chromatography and recrystallisation.
[19] US 2007/0100148 discloses a process for preparing Anastrozole wherein 1-bromomethyl-3,5-bis(2-cyanoisopropyl)toluene is reacted with the sodium salt of 1,2,4-triazole. The product is purified by aqueous work-up, filtration over silica gel and recrystallisation. While the obtained Anastrozole has a purity of 99.97% by HPLC, and yields are quite low.
[20] US 2008/0177081 Al provides an improved, efficient process for the preparation of Anastrozole. Synthesis of Anastrozole without reducing the temperature below 0° C, easily operation, devoid of using carcinogenic reagent, and reducing the level of isomeric impurity of the Anastrozole to 0.1% are advantageous with respect to industrial application. Further, this invention provides an improved process for preparing the 3,5-bis(bromomethyl)toluene from the 1,3,5-trimethylbenzene without the usage of toxic reagents, such as benzoyl peroxide and carbon tetrachloride.
[21] It is difficult to manufacture Anastrozole in the required quality by following simple crystallization. The known processes comprise reaction of bromomethyl compound of formula III with 1,2,4 triazole or its salt have been found to give isoanastrozole isomer of formula II in unacceptable amounts. This impurity along with other impurities is difficult to remove by usual working up procedures leading to extensive and expensive purification processes. Most of the processes disclose the purification of Anastrozole to remove unwanted isoanastrozole impurity of formula II 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. WO 2009/010991 invention describe a simple and commercially attractive process to remove isomer impurity and prepare highly pure Anastrozole.
[22] WO2007105231 invention relates to an improved process for the preparation of Anastrozole having enhanced purity from crude Anastrozole having isomeric impurity up to less than 1%. This process circumvents chromatography in the purification of Anastrozole of high purity. This process provides crude Anastrozole having minimum isomeric impurity, which has not been achieved in the earlier reported processes.
[23] US8058302B2 in 2011, described an improved process for the preparation of pure Anastrozole free from impurities arising due to hydrolysis of cyano groups during the course of the preparation of Anastrozole.
[24] Thus, the known processes to synthesize Anastrozole are tedious, requires sophisticated and costly facilities, result in lesser yield, less regioselective, requires costly purification techniques and toxic organic solvents. There is still required an industrial process for the preparation of Anastrozole wherein the process is simple, requires less facilities, cheaper in cost, more selective in terms of isomers, provide high purity product with, having economic significance and environmentally safer.
[25] The present invention discloses a novel process for the preparation of Anastrozole offering a simple process, which is more selective in terms of isomer results into higher yield, needs lesser facility for managing reaction condition, devoid of costly purification technologies and requires lesser organic solvent which reduce the burden on the environment.

SUMMARY OF THE INVENTION
[26] The present invention provides an improved process for the preparation of Anastrozole, compound of formula (I)

Formula (I).
[27] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I):

Formula (I),
the process comprising steps of:
(i) reacting a compound of formula (IA) with N-bromo succinimide

Formula (IA)
to provide a compound of formula (IB)

Formula (IB)
(ii) reacting compound of formula (IB) with sodium cyanide to provide a compound of formula (IC)

Formula (IC);
(iii) reacting compound of formula (IC) with methyl iodide to provide a compound of formula (ID)

Formula (ID);
(iv) reacting compound of formula (ID) with N-Bromo Succinimide to provide a compound of formula (IE)

Formula (IE);
(v) reacting the compound of formula (IE) and sodium 1,2,4 triazole to provide Anastrozole, compound of formula (I); and
(vi) purifying the compound of formula (I) by washing the compound of formula (I) with isopropyl alcohol.

[28] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein, chlorobenzene is used as solvent in reaction of step (i).
[29] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein azobisisobutyronitrile (AIBN) is used as a catalyst in reaction of step (i).
[30] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (i) is carried out at 50 to 80 oC.
[31] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein dichloromethane (DCM) is used as solvent in reaction of step (ii).
[32] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein tetrabutylammonium bromide (TBAB) is used as a catalyst in reaction of step (ii).
[33] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (ii) is carried out at 25 to 50 oC.
[34] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein dimethylformamide is used as solvent in reaction of step (iii).
[35] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein sodium hydride is used as strong base catalyst in reaction of step (iii).
[36] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (iii) is carried out at 0 to 50 oC.
[37] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein acetonitrile is used as solvent in reaction of step (iv).
[38] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein azobisisobutyronitrile is used as a catalyst in reaction of step (iv).
[39] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (iv) is carried out at 50 to 80 oC.
[40] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein dimethylformamide is used as solvent in reaction of step (v).
[41] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (v) is carried out at 0 to 25 oC.
[42] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of the step (vi) comprises steps of:
(i) dissolving the Anastrozole, compound of formula (I) obtained in step (v) in solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, water and mixture thereof at suitable temperature;
(ii) filtering the solution obtained in step (i);
(iii) washing the crystalline fraction obtained in step (ii) with solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, water and mixture thereof at suitable temperature; and
(iv) isolating the purified Anastrozole, compound of formula (I) by drying;
wherein suitable temperature for step (i) and (iii) is temperature about 50 to 100 oC.
[43] In one aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I), wherein the reaction molar yield is more than 90%.
[44] In another aspect, the present invention provides an improved process for the preparation of a compound of formula (IB):

Formula (IB),
the process comprising of reacting a compound of formula (IA) with N-bromo succinimide

Formula (IA)
to provide a compound of formula (IB).
[45] In one aspect, the present invention provides an improved process for the preparation of a compound of formula (IB), wherein chlorobenzene is used as solvent.
[46] In one aspect, the present invention provides an improved process for the preparation of a compound of formula (IB), wherein azobisisobutyronitrile is used as a catalyst.
[47] In one aspect, the present invention provides an improved process for the preparation of a compound of formula (IB), wherein the reaction is carried out at 50 to 80 oC.
[48] In another aspect, the present invention provides an improved process for the preparation of a compound of formula (IC):

Formula (IC);
the process comprising of reacting compound of formula (IB) with sodium cyanide

Formula (IB);
to provide a compound of formula (IC).
[49] In one aspect, the present invention provides an improved process for the preparation of a compound of formula (IC), wherein dichloromethane (DCM) is used as solvent.
[50] In one aspect, the present invention provides an improved process for the preparation of a compound of formula (IC), wherein tetrabutylammonium bromide (TBAB) is used as a catalyst.
[51] In one aspect, the present invention provides an improved process for the preparation of a compound of formula (IC), wherein the reaction is carried out at 25 to 50 oC.
[52] In another aspect, the present invention provides an improved process for the preparation of a compound of formula (ID):

Formula (ID)
reacting compound of formula (IC) with methyl iodide
to provide a compound of formula (ID)

Formula (IC);
to provide a compound of formula (ID).
[53] In one aspect, the present invention provides an improved process for the preparation of a compound of formula (ID), wherein dimethylformamide is used as solvent.
[54] In one aspect, the present invention provides an improved process for the preparation of a compound of formula (ID), wherein sodium hydride is used as strong base catalyst.
[55] In one aspect, the present invention provides an improved process for the preparation of a compound of formula (ID), wherein the reaction is carried out at 0 to 50 oC.
[56] In another aspect, the present invention provides a process for the preparation of substantially pure Anastrozole, compound of formula (I) comprising steps of:
(i) dissolving the Anastrozole in solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, water and mixture thereof at suitable temperature;
(ii) filtering the solution obtained in step (i);
(iii) washing the crystalline fraction obtained in step (ii) with solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, water and mixture thereof at suitable temperature; and
(iv) isolating the substantially pure Anastrozole by drying.
[57] In one aspect, the present invention provides a process for the preparation of substantially pure Anastrozole, compound of formula (I), wherein suitable temperature for step (i) and (iii) is temperature about 50 to 100 oC.
[58] In one aspect, the present invention provides a process for the preparation of substantially pure Anastrozole, compound of formula (I), wherein substantial pure Anastrozole, compound of formula (I) is having HPLC purity equal to or greater than 99.5%.
[59] In another aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I); wherein the process is free from the use of chromatographic techniques for purifying intermediates as well as the final product.
[60] In another aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I); wherein the process is free from the use of toxic and harmful reagents and solvents and provides an environmentally friendly and safer process.
[61] In another aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I); wherein the process provides compound of formula (I) with higher purity and improved yield as compared to existing processes.
[62] In another aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I); wherein the process shows improved selectivity for the desired isomer of the compound of formula (I) with negligible isomeric impurity.
[63] In another aspect, the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I); wherein the process is best suited to industrial production of Anastrozole, compound of formula (I) in terms of economic significance, purity, isomer selectivity and yield.

DETAILED DESCRIPTION OF THE INVENTION
Definitions
[64] The term "reaction conditions" is intended to refer to the physical and/or environmental conditions under which a chemical reaction proceeds. Examples of reaction conditions include, but are not limited to, one or more of following: reaction temperature, solvent, pH, pressure, reaction time, mole ratio of reactants, the presence of an acid base, or catalyst, radiation, etc. Reaction conditions may be named after the particular chemical reaction in which the conditions are employed, such as, coupling conditions, hydrogenation conditions, acylation conditions, reduction conditions, etc. Reaction conditions for most reactions are generally known to those skilled in the art or can be readily obtained from the literature. Exemplary reaction conditions sufficient for performing the chemical transformations provided herein can be found throughout, and in particular, the examples below. It is also contemplated that the reaction conditions can include reagents in addition to those listed in the specific reaction.
[65] The term "catalyst" refers to a chemical substance that enables a chemical reaction to proceed at a usually faster rate or under different conditions (such as at a lower temperature) than otherwise possible.
[66] The term "substantially pure" refers to a HPLC purity equal to or greater than 99.5%.
[67] In addition, abbreviations as used herein have respective meanings as follows:
h=hour(s)
mL= milliliter
equiv.= equivalent
g=gram
min=minutes
°C=degree centigrade
IR=infrared
NMR=Nuclear magnetic resonance
LCMS= Liquid chromatography–mass spectrometry
ESI-MS = Electrospray Ionization Mass Spectrometry
AIBN=Azobisisobutyronitrile
NBS=N-bromo succinimide
NMT=Not more than
DCM=dichloromethane
TBAB=tetrabutylammonium bromide
DMF= dimethylformamide
MeI=methyl iodide
Aq.=aqueous
RBF=round bottom flask
[68] The present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I)

Formula (I).
[69] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I):

Formula (I),
the process comprising steps of:
(i) reacting a compound of formula (IA) with N-bromo succinimide

Formula (IA)
to provide a compound of formula (IB)

Formula (IB)
(ii) reacting compound of formula (IB) with sodium cyanide to provide a compound of formula (IC)

Formula (IC);
(iii) reacting compound of formula (IC) with methyl iodide to provide a compound of formula (ID)

Formula (ID);
(iv) reacting compound of formula (ID) with N-Bromo Succinimide to provide a compound of formula (IE)

Formula (IE);
(v) reacting the compound of formula (IE) and sodium 1,2,4 triazole to provide Anastrozole, compound of formula (I); and
(vi) purifying the compound of formula (I) by washing the compound of formula (I) with isopropyl alcohol.
[70] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein, chlorobenzene is used as solvent in reaction of step (i).
[71] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein azobisisobutyronitrile (AIBN) is used as a catalyst in reaction of step (i).
[72] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (i) is carried out at 50 to 80 oC.
[73] In one preferred embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (i) is carried out at 65 to 80 oC.
[74] In one preferred embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (i) is carried out for about 30 minutes to 3 hours; preferably for 1 to 2 hours.
[75] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein dichloromethane (DCM) is used as solvent in reaction of step (ii).
[76] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein tetrabutylammonium bromide (TBAB) is used as a catalyst in reaction of step (ii).
[77] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (ii) is carried out at 25 to 50 oC.
[78] In one preferred embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (ii) is carried out at 40 to 45 oC.
[79] In one preferred embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (ii) is carried out for about 4 to 14 hours; preferably 8 to 12 hours; more preferably 8 to 10 hours.
[80] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein dimethylformamide is used as solvent in reaction of step (iii).
[81] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein sodium hydride is used as strong base catalyst in reaction of step (iii).
[82] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (iii) is carried out at 0 to 50 oC.
[83] In one preferred embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (iii) is carried out at 0 to 35 oC.
[84] In one preferred embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (iii) is carried out for about 30 minutes to 3 hours; preferably for 1 to 2 hours.
[85] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein acetonitrile is used as solvent in reaction of step (iv).
[86] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein azobisisobutyronitrile is used as a catalyst in reaction of step (iv).
[87] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (iv) is carried out at 50 to 80 oC.
[88] In one preferred embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (iv) is carried out at 75 to 80 oC.
[89] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (iv) is carried out for about 1 to 4 hours; preferably 2 to 3 hours.
[90] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein dimethylformamide is used as solvent in reaction of step (v).
[91] In one preferred embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (v) is carried out at 0 to 25 oC.
[92] In one preferred embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (v) is carried out at 0 to 15 oC.
[93] In one preferred embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of step (v) is carried out for about 1 to 4 hours; preferably 2 to 3 hours.
[94] In another embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein reaction of the step (vi) comprises steps of:
(i) dissolving the Anastrozole, compound of formula (I) obtained in step (v) in solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, water and mixture thereof at suitable temperature;
(ii) filtering the solution obtained in step (i);
(iii) washing the crystalline fraction obtained in step (ii) with solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, water and mixture thereof at suitable temperature; and
(iv) isolating the purified Anastrozole, compound of formula (I) by drying;
wherein suitable temperature for step (i) and (iii) is temperature about 50 to 100 oC.
[95] In one embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I), wherein the reaction molar yield is more than 90%.
[96] In another embodiment, the present invention discloses an improved process for the preparation of a compound of formula (IB):

Formula (IB),
the process comprising of reacting a compound of formula (IA) with N-bromo succinimide

Formula (IA)
to provide a compound of formula (IB).
[97] In one embodiment, the present invention discloses an improved process for the preparation of a compound of formula (IB), wherein chlorobenzene is used as solvent.
[98] In one embodiment, the present invention discloses an improved process for the preparation of a compound of formula (IB), wherein azobisisobutyronitrile is used as a catalyst.
[99] In one embodiment, the present invention discloses an improved process for the preparation of a compound of formula (IB), wherein the reaction is carried out at 50 to 80 oC.
[100] In one preferred embodiment, the present invention discloses an improved process for the preparation of a compound of formula (IB), wherein the reaction is carried out at 65 to 80 oC.
[101] In one preferred embodiment, the present invention discloses an improved process for the preparation of a compound of formula (IB), wherein the reaction is carried out for about 30 minutes to 3 hours; preferably for 1 to 2 hours.
[102] In another embodiment, the present invention discloses an improved process for the preparation of a compound of formula (IC):

Formula (IC);
the process comprising of reacting compound of formula (IB) with sodium cyanide

Formula (IB);
to provide a compound of formula (IC).
[103] In one embodiment, the present invention discloses an improved process for the preparation of a compound of formula (IC), wherein dichloromethane (DCM) is used as solvent.
[104] In one embodiment, the present invention discloses an improved process for the preparation of a compound of formula (IC), wherein tetrabutylammonium bromide (TBAB) is used as a catalyst.
[105] In one embodiment, the present invention discloses an improved process for the preparation of a compound of formula (IC), wherein the reaction is carried out at 25 to 50 oC.
[106] In one preferred embodiment, the present invention discloses an improved process for the preparation of a compound of formula (IC), wherein the reaction is carried out at 40 to 45 oC.
[107] In one preferred embodiment, the present invention discloses an improved process for the preparation of a compound of formula (IC), wherein the reaction is carried out for about 4 to 14 hours; preferably 8 to 12 hours; more preferably 8 to 10 hours.
[108] In another embodiment, the present invention discloses an improved process for the preparation of a compound of formula (ID):

Formula (ID)
reacting compound of formula (IC) with methyl iodide
to provide a compound of formula (ID)

Formula (IC);
to provide a compound of formula (ID).
[109] In one embodiment, the present invention discloses an improved process for the preparation of a compound of formula (ID), wherein dimethylformamide is used as solvent.
[110] In one embodiment, the present invention discloses an improved process for the preparation of a compound of formula (ID), wherein sodium hydride is used as strong base catalyst.
[111] In one preferred embodiment, the present invention discloses an improved process for the preparation of a compound of formula (ID), wherein the reaction is carried out at 0 to 50 oC.
[112] In one preferred embodiment, the present invention discloses an improved process for the preparation of a compound of formula (ID), wherein the reaction is carried out at 0 to 35 oC.
[113] In one preferred embodiment, the present invention discloses an improved process for the preparation of a compound of formula (ID), wherein the reaction is carried out for about 30 minutes to 3 hours; preferably for 1 to 2 hours.
[114] In another embodiment, the present invention discloses a process for the preparation of substantially pure Anastrozole, compound of formula (I) comprising steps of:
(i) dissolving the Anastrozole in solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, water and mixture thereof at suitable temperature;
(ii) filtering the solution obtained in step (i);
(iii) washing the crystalline fraction obtained in step (ii) with solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, water and mixture thereof at suitable temperature; and
(iv) isolating the substantially pure Anastrozole by drying.
[115] In one embodiment, the present invention discloses a process for the preparation of substantially pure Anastrozole, compound of formula (I), wherein suitable temperature for step (i) and (iii) is temperature about 50 to 100 oC.
[116] In one embodiment, the present invention discloses a process for the preparation of substantially pure Anastrozole, compound of formula (I), wherein substantial pure Anastrozole, compound of formula (I) is having HPLC purity equal to or greater than 99.5%.
[117] In another embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I); wherein the process is free from the use of chromatographic techniques for purifying intermediates as well as the final product.
[118] In another embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I); wherein the process is free from the use of toxic and harmful reagents and solvents and provides an environmentally friendly and safer process.
[119] In another embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I); wherein the process provides compound of formula (I) with higher purity and improved yield as compared to existing processes.
[120] In another embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I); wherein the process shows improved selectivity for the desired isomer of the compound of formula (I) with negligible isomeric impurity.
[121] In another embodiment, the present invention discloses an improved process for the preparation of Anastrozole, compound of formula (I); wherein the process is best suited to industrial production of Anastrozole, compound of formula (I) in terms of economic significance, purity, isomer selectivity and yield.

EXAMPLE:
[122] The invention can be better understood with the help of the below example. Anastrozole, compound of formula (I) could be prepared through the reaction claimed in the present patent application. A detailed protocol is provided herein below which makes a person skilled in the art to prepare Anastrozole, compound of formula (I) using the claimed invention.
Step-1: Synthesis of 1,3-Bis(bromomethyl)-5-methylbenzene:

[123] Mesitylene (100.0 g, 0.83 mole, 1.0 equivalent) was added to 1500 mL of chlorobenzene. Azobisisobutyronitrile (6.84 g, 0.0416 mole, 0.05 equivalent) was added to the reaction mixture and heated the reaction mixture at 65-70 oC. N-bromo succinimide (310.9 g, 1.747 mole, 2.1 equivalent) was added to the reaction mixture in portion wise. First, 77.7 g N-bromo succinimide was added and stirred the reaction mixture at 65-70 oC for 20-30 minutes. Next portion N-bromo succinimide (77.7 g) was added and stirred the reaction mixture at 65-70 oC for 20-30 minutes. Other two batches of N-bromo succinimide (77.7 g) were added and stirred the reaction mixture at 70-80 oC for 1 hour. After completion of reaction, reaction mass was cooled, filtered and washed with 100 mL of chlorobenzene. Then added 5% sodium sulphite solution to the filtrate. Organic layer was washed with water and filtered through 0.45-micron filter. Reaction mass was distilled out completely under vacuum (Bath Temperature note more than 65 °C). Dichloromethane (50.0 mL) and Isopropyl alcohol (500.0 mL) were added to the reaction mixture and stirred at 5-10 oC for 3-4 hours. Reaction mixture was filtered and washed with chilled isopropyl alcohol (25.0 mL). Reaction mixture was dried under vacuum to get the desired compound 1,3-Bis(bromomethyl)-5-methylbenzene as white solid (110 g).
Yield: 47.56%.
1H NMR (400 MHz, CDCl3) δ: 2.34 (s, 3H, CH3), 4.44 (s, 4H, CH2), 7.14 (s, 2H, Ar-H), 7.22 (s, 1H, Ar-H).
ESI m/z: 279.1 [M+H] +.
IR: Vmax (cm-1): 2363, 1778, 1608, 1455, 1435, 1378, 1300, 1206, 1158, 1124, 1036, 954, 871, 854, 702.

Step-2: Synthesis of 2,2'-(5-Methyl-1,3-phenylene)diacetonitrile:

[124] 1,3-Bis(bromomethyl)-5-methylbenzene (product of step-1) (100.0 g, 0.3597 mole, 1.0 equivalent) was dissolved in 400 mL dichloromethane. tetrabutylammonium bromide (2.55 g, 0.0079 mole, 0.022 equivalent), sodium cyanide (70.51 g, 1.438 mole, 4.0 equivalent) and 200 mL potable water were added to the reaction mixture. The reaction mixture was heated at 40-45 oC for 8 hours. After completion, reaction mixture was cooled and potable water (300 mL) was added and stirred for 20-30 minutes. Organic layer was separated and aqueous layer was extracted with dichloromethane (200.0 mL). Mixed the organic layers and distilled out under vacuum. Organic compound was dissolved in 400.0 mL isopropyl alcohol and stirred at 50-60 oC for 60-70 minutes. Reaction mass was cooled and filtered, washed with 25.0 mL of isopropyl alcohol. Dried the reaction mass under vacuum to get the desired compound 2,2'-(5-Methyl-1,3-phenylene)diacetonitrile as white to yellow solid (50 g).
Yield: 81.7 %.
1H NMR (400 MHz, CDCl3) δ: 2.38 (s, 3H, CH3), 3.73 (s, 4H, CH2), 7.08 (s, 2H, Ar-H), 7.13 (s, 1H, Ar-H).
ESI m/z: 169.1 [M+H]-.
IR: Vmax (cm-1): 2936, 2914, 2361, 2249, 1603, 1462, 1414, 1325, 1290, 1250, 1220, 1198, 1042, 997, 971, 933, 914, 891, 707, 676.

Step-3: Synthesis of 2,2'-(5-Methyl-1,3-phenylene)bis(2-methylpropanenitrile):

[125] 2,2'-(5-Methyl-1,3-phenylene)diacetonitrile (100.0 g, 0.588 mole, 1.0 equivalent) was dissolved in dimethylformamide (1400.0 mL). Methyl iodide (416.95 g, 2.938 mole, 5.0 equivalent) was added to the reaction mixture. Further, sodium hydride (117.50 g, 2.938 mole, 5.0 equivalent) was added in portions to the reaction mixture at 0-5 oC temperature. First, 29.37 g sodium hydride was added and stirred the reaction mixture at 0-5 oC for 20-30 minutes. Remaining sodium hydride was added in another three portion of 29.37 g each. Reaction mixture was stirred at 25-35 oC for 60 minutes. After completion of reaction, ethyl acetate (1500.0 mL) and water (1500.0 mL) was added to the reaction mixture and separated the organic layer. Aqueous layer was extracted two times with ethyl acetate. Then, the organic layer was mixed and 25% sodium chloride solution was added. Organic layer was separated and 10.g activated carbon was added to it. Organic compound was filtered through Hyflo® and washed with 100.0 mL ethyl acetate. Organic solvent was distilled out under vacuum to dry the organic compound. The organic compound was dissolved in 300.0 mL of isopropyl alcohol and stirred for 2 hours at 25-35 oC. Filtered the reaction mas and washed with 50.0 mL isopropyl alcohol. The mixture was dried under vacuum for 10-12 hours at 50-60 oC. The dried material was dissolved in 1000.0 mL methanol and stirred at 50-60 oC for 60 minutes. After cooling reaction mass was filtered and washed with 50.00 mL methanol and dried under vacuum to get the desired compound 2,2'-(5-methyl-1,3-phenylene)bis(2-methylpropanenitrile) as white solid (110 g).
Yield: 82.7%.
1H NMR (400 MHz, CDCl3) δ: 1.73 (s, 12H, CH3), 2.41 (s, 3H, CH3), 7.25 (s, 2H, Ar-H), 7.32 (s, 1H, Ar-H).
ESI m/z: 244.4 [M+NH4] +.
IR: Vmax (cm-1): 2984, 2946, 2918, 2238, 1601, 1436, 1389, 1370, 1293, 1226, 1204, 1139, 1000, 961, 867.

Step-4: Synthesis of 2,2'-(5-(Bromomethyl)-1,3-phenylene)bis(2-methylpropanenitrile):

[126] 2,2'-(5-Methyl-1,3-phenylene)bis(2-methylpropanenitrile) (100.0 g, 0.441 mole, 1.0 equivalent) was dissolved in 1000.0 mL acetonitrile. N-Bromo Succinimide (94.37 g, 0.530 mole, 1.2 equivalent), azobisisobutyronitrile (1.45 g, 0.008 mole, 0.02 equivalent) was added to the reaction mixture and stirred for 10-20 minutes. Reaction mixture was stirred at 75-80 oC for 2 hours. After completion of reaction, reaction mixture was cooled and 5.0% sodium sulfite solution was added and stirred for 10-20 minutes. 700.0 mL toluene was added to the reaction mixture and stirred for 10-20 minutes. Organic layer was separated and washed with water and filtered through 0.20-micron filter. Toluene was distilled out completely under vacuum.

Step-5: Synthesis of 2,2'-(5-((1H-1,2,4-triazol-1-yl)methyl)-1,3-phenylene)bis(2-methylpropanenitrile):

[127] Compound (IE) was dissolved in 200.0 mL dimethylformamide and stirred for 10-20 min. In another round bottomed flask sodium 1,2,4 triazole (60.35 g, 0.662 mole, 1.5 equivalent) was dissolved in 200.0 mL dimethylformamide. Solution of 3,5-Bis(2-cyanoprop-2-yl)benzylbromide (product of step-4) was added into sodium 1,2,4 triazole solution at 0-10 oC and stirred at 0-15 oC for 120-150 minutes. Reaction mixture was maintained at this temperature for 1 hour. after completion of reaction, mixture was filtered and washed with toluene (200.0 x 2 mL). After that reaction mass was cooled to 5-10 oC and 10.0% sodium chloride solution was added slowly over 60-90 minutes. Reaction mixture was stirred for 10-20 min at 25-35 oC. Organic layer was separated and aq. layer was washed with toluene (2 x 500.0 mL). 10% sodium bisulfate solution was added to the organic layer and stirred for 10-20 minutes. Organic layer was separated and hydrochloric acid solution was added to the organic layer and stirred for 10-20 minutes. Hydrochloric acid solution was added to the organic layer and stirred for 10-20 minutes. Organic layer was separated and again charged with hydrochloric acid solution. Aqueous layer was separated and combined aqueous layer was charged with 250.0 mL dichloromethane and pH was adjusted to 7.0-8.0 by using 15.0 % sodium hydroxide solution. Aqueous layer was separated and extracted again with dichloromethane. Organic layer was separated and combine both the organic layers and washed with water. In separated organic layer 5.0 g activated carbon was added and reaction mass was filtered through Hyflo® followed by filter through 0.20-micron. Organic layer was washed with 100.0 mL dichloromethane and distilled out under vacuum. The compound was washed with isopropyl alcohol and dried under vacuum to get the desired compound 2,2'-(5-((1H-1,2,4-triazol-1-yl) methyl)-1,3-phenylene) bis(2-methylpropanenitrile) (Anastrozole) as white solid (80 g).
Yield: 61.71%.
1H NMR (400 MHz, CDCl3) δ: 1.73 (s, 12H, CH3), 5.40 (s, 2H, CH2), 7.33 (d, 2H, Ar-H), 7.54 (t, 1H, Ar-H), 8.01 (s, 1H, Ar-H), 8.15 (s, 1H, Ar H).
ESI m/z: 294.0 [ M + H] +.
IR: Vmax (cm-1): 3102, 2984, 2974, 2235, 1653, 1606, 1559, 1500, 1475, 1457, 1429, 1424, 1388, 1368, 1359, 1351, 1273, 1221, 1206, 1194, 1161, 1151, 970, 959, 938, 913, 894, 884, 875, 791, 763, 713, 664.

Step-6: Purification of Anastrozole:
[128] 2,2'-(5-((1H-1,2,4-triazol-1-yl) methyl)-1,3-phenylene) bis(2-methylpropanenitrile) (Anastrozole) obtained in step-5 (100.0 g, 1.0 equivalent) was dissolved in 800.0 mL isopropyl alcohol. Reaction mixture was stirred at 60-70 oC for 30-60 minutes. Reaction mixture was filtered through 0.20-micron filter and washed with hot isopropyl alcohol (50.0 mL). Reaction mixture was cooled to 0-5 oC and filtered. Reaction mass was washed with 50.0 mL chilled isopropyl alcohol. The organic compound was dried under vacuum for 10-12 hours at 35-45 oC to get analytically pure Anastrozole as white solid (90 g).
Yield: 90%.

ADVANTAGES OF THE PRESENT INVENTION:
[129] The process disclosed in the present invention is devoid of toxic and harmful reagents; and therefore, provides an environmentally friendly and safer process for the preparation of Anastrozole, compound of formula (I).
[130] The process disclosed in the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I); wherein, the process requires lesser facilities or the reaction can be carried out without stringent reaction conditions at mild reaction conditions.
[131] The process disclosed in the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I); wherein the process is free from tedious, time consuming and costly column chromatographic based purification. Further, the process is free from use of large volumes of toxic organic solvents.
[132] The process disclosed in the present invention provides an improved process for the preparation of Anastrozole, compound of formula (I); wherein the reaction avoids/minimizes hydrolysis of cyano group present in one of the intermediates during synthesis of Anastrozole; which resultantly avoid formation of impurities in the end products and eliminates the need of tedious, time consuming and costly column chromatographic based purification.
[133] The process disclosed in present invention uses reagents such as NBS and acetonitrile solvent (environmentally friendly); unlike the reported processes which uses benzoyl peroxide, AIBN, m-chloro benzoyl peroxide, sulphuric acid, 1,1,2-ethylene trichloride, carbon tetrachloride, nitrobenzene and chlorobenzene which are toxic and harmful to the environment.
[134] The process disclosed in present invention is capable of providing Anastrozole without reducing the temperature below 0 °C in the whole process which makes the claimed process simple. On the other side N-alkylation of 1,2,4-triazole with 1-bromomethyl-3,5-bis(2-cyanoisopropyl) toluene requires low temperatures i.e. below -20°C. Such stringent reaction condition is not suitable for an industrial production.
[135] The process disclosed in present invention is capable of providing Anastrozole with the isomeric impurity less than 0.1% which is particularly suitable for industrial production (as per ICH Q-11 guidelines, known impurity limits 0.15% is for Anastrozole). In existing processes, sometimes the reaction of bromo derivative (3,5-Bis(2-Cyanoprop-2yl)benzyl) bromide) with 1,2,4 triazole or its salt have been found to give isoanastrozole isomer in unacceptable amounts. This impurity along with other impurities is difficult to remove by usual working up procedures leading to extensive and expensive purification processes. Most of the processes disclose the purification of anastrozole to remove unwanted isoanastrozole impurity 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.
[136] The process disclosed in present invention provides a yield between 80-90% which is quite good as compared to processes known in the public domain.
[137] The process disclosed in present invention is very simple in respect to purification of crude Anastrozole. In literature, crude anastrozole is purified by selective extraction using mixture of solvents such as toluene, linear, branched or cyclic C5-8 hydrocarbon, water, methylpyrrolidine and 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 layer to precipitate anastrozole which is isolated by filtration. It is further recrystallized in isopropyl alcohol and heptane to get pure anastrozole. This purification process requires lot of efforts. Our manufacturing process doesn’t require mixture of solvents for purification of crude anastrozole.
[138] The process disclosed in present invention is devoid aqueous work up operations, column chromatography and recrystallization which are required by the processes known in the public domain.
, C , C , Claims:I/We Claim:
1. An improved process for the preparation of Anastrozole, compound of formula (I):

Formula (I),
the process comprising steps of:
(i) reacting a compound of formula (IA) with N-bromo succinimide

Formula (IA)
to provide a compound of formula (IB)

Formula (IB)
(ii) reacting compound of formula (IB) with sodium cyanide to provide a compound of formula (IC)

Formula (IC);
(iii) reacting compound of formula (IC) with methyl iodide to provide a compound of formula (ID)

Formula (ID);
(iv) reacting compound of formula (ID) with N-Bromo Succinimide to provide a compound of formula (IE)

Formula (IE);
(v) reacting the compound of formula (IE) and sodium 1,2,4 triazole to provide Anastrozole, compound of formula (I); and
(vi) purifying the compound of formula (I) by washing the compound of formula (I) with isopropyl alcohol.
2. The process claimed in the claim 1, wherein chlorobenzene is used as solvent in reaction of step (i).
3. The process claimed in the claim 1, wherein azobisisobutyronitrile (AIBN) is used as a catalyst in reaction of step (i).
4. The process claimed in the claim 1, wherein reaction of step (i) is carried out at 50 to 80 oC.
5. The process claimed in the claim 1, wherein dichloromethane (DCM) is used as solvent in reaction of step (ii).
6. The process claimed in the claim 1, wherein tetrabutylammonium bromide (TBAB) is used as a catalyst in reaction of step (ii).
7. The process claimed in the claim 1, wherein reaction of step (ii) is carried out at 25 to 50 oC.
8. The process claimed in the claim 1, wherein dimethylformamide is used as solvent in reaction of step (iii).
9. The process claimed in the claim 1, wherein sodium hydride is used as strong base catalyst in reaction of step (iii).
10. The process claimed in the claim 1, wherein reaction of step (iii) is carried out at 0 to 50 oC.
11. The process claimed in the claim 1, wherein acetonitrile is used as solvent in reaction of step (iv).
12. The process claimed in the claim 1, wherein azobisisobutyronitrile is used as a catalyst in reaction of step (iv).
13. The process claimed in the claim 1, wherein reaction of step (iv) is carried out at 50 to 80 oC.
14. The process claimed in the claim 1, wherein dimethylformamide is used as solvent in reaction of step (v).
15. The process claimed in the claim 1, wherein reaction of step (v) is carried out at 0 to 25 oC.
16. The process claimed in the claim 1, wherein the step (vi) comprises steps of:
(i) dissolving the Anastrozole, compound of formula (I) obtained in step (v) in solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, water and mixture thereof at suitable temperature;
(ii) filtering the solution obtained in step (i);
(iii) washing the crystalline fraction obtained in step (ii) with solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, water and mixture thereof at suitable temperature; and
(iv) isolating the purified Anastrozole, compound of formula (I) by drying;
wherein suitable temperature for step (i) and (iii) is temperature about 50 to 100 oC.
17. The process claimed in the claim 1, wherein the reaction molar yield is more than 90%.
18. An improved process for the preparation of a compound of formula (IB):

Formula (IB),
the process comprising of reacting a compound of formula (IA) with N-bromo succinimide

Formula (IA)
to provide a compound of formula (IB).
19. The process claimed in the claims 18, wherein chlorobenzene is used as solvent.
20. The process claimed in the claims 18, wherein azobisisobutyronitrile is used as a catalyst.
21. The process claimed in the claims 18, wherein reaction is carried out at 50 to 80 oC.
22. An improved process for the preparation of a compound of formula (IC):

Formula (IC);
the process comprising of reacting compound of formula (IB) with sodium cyanide

Formula (IB);
to provide a compound of formula (IC).
23. The process claimed in the claims 22, wherein dichloromethane (DCM) is used as solvent.
24. The process claimed in the claims 22, wherein tetrabutylammonium bromide (TBAB) is used as a catalyst.
25. The process claimed in the claims 22, wherein reaction is carried out at 25 to 50 oC.
26. An improved process for the preparation of a compound of formula (ID):

Formula (ID)
reacting compound of formula (IC) with methyl iodide
to provide a compound of formula (ID)

Formula (IC);
to provide a compound of formula (ID).
27. The process claimed in the claims 26, wherein dimethylformamide is used as solvent.
28. The process claimed in the claims 26, wherein sodium hydride is used as strong base catalyst.
29. The process claimed in the claims 26, wherein reaction is carried out at 0 to 50 oC.
30. A process for the preparation of substantially pure Anastrozole, compound of formula (I) comprising steps of:
(i) dissolving the Anastrozole in solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, water and mixture thereof at suitable temperature;
(ii) filtering the solution obtained in step (i);
(iii) washing the crystalline fraction obtained in step (ii) with solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, water and mixture thereof at suitable temperature; and
(iv) isolating the substantially pure Anastrozole by drying.
31. The process of the claim 30, wherein suitable temperature for step (i) and (iii) is temperature about 50 to 100 oC.
32. The process of the claim 30, wherein substantial pure Anastrozole, compound of formula (I) is having HPLC purity equal to or greater than 99.5%.
This 31st day of January 2025.
Jaya Makhija [IN/PA-3488]
Agent/Attorney for the Applicant