FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention: PURE INTERMEDIATE

2. Applicants):
(a) NAME:
(b) NATIONALITY:
(c) ADDRESS:

MYLAN INDIA PRIVATE LIMITED
An Indian Company.
Plot 1A/2, MIDC. Industrial Estate, Taloja,
Panvel, District Raigad, Maharashtra-410208, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of the Invention
The present invention relates to an improved process for the preparation of Letrozole (I) and its synthetic intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III). In particular, it relates to a process to prepare Letrozole and its intermediates (III) substantially free from regioisomeric impurities.
Background of the Invention
Letrozole, chemically named as 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl)]benzonitri!e (I) is one of a new class of drugs, known as aromatase inhibitors, which function by reducing oestrogen levels in postmenopausal women as many breast cancers increase in size by utilising the hormone oestrogen. In women who have undergone menopause, the main source of oestrogen is through the conversion of androgens (sex hormones produced by the adrenal glands) into oestrogen. The conversion process, which is known as aromatisation, happens mainly in the fatty tissues of the body and is catalysed by an enzyme called aromatase. Letrozole blocks this aromatisation process and reduces the amount of oestrogen in the body and consequently Letrozole is marketed as a type of hormonal therapy that is used in the treatment of breast cancer in women.

Letrozole (I) (II)
Letrozole and processes to prepare it were first described in patent US 4,978,672. The synthesis of Letrozole proceeded via reaction of intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) with 4-fluorobenzonitrile (IV) in the presence of a catalyst, potassium tert-butoxide. The preparation of intermediate (III) was achieved

by reaction of 4-bromomethylbenzonitrile with 1,2,4-triazole in a mixture of chloroform and acetonitrile at reflux, followed by the purification of the product (III) by column chromatography. It was found that during the preparation of intermediate (III), an undesired regioisomer, namely 4-[(1-(1,3,4-triazolyl)methyl]benzonttrile (V), was formed in about 20-25% yield. Consequently, this leads to an uneconomical loss of yield and to a difficult and inconvenient purification of intermediate (III) which was required to remove the regioisomeric impurity (V). In addition, complete purification was not possible and the impurity (V) was carried through the synthesis resulting in the formation of regioisomer (II) in the synthetic step to prepare Letrozole. As a consequence, the final purification of Letrozole had to involve removal of impurity (II). These two purifications were very difficult and a substantial quantity of material was lost during the purifications by column chromatography. In addition, removal of the impurities by column chromatography vastly increased the solvent consumption of the process and purification using column chromatography is not a practical approach for the industrial production of Letrozole or its intermediates.



4-[(1 -(1,2>4-triazol-yl)methy[Ibenzonitrile (III)


4-Fluorobenzonitrile (IV)

(V)

Another process for the preparation of Letrozole, disclosed in patent application WO 2005/047269, has recognised that the removal of the undesired regioisomers by column chromatography is a problem. The disclosed method for separation of unwanted impurity (V) from the intermediate (III) is by preparation of its hydrochloride salt which is relatively less soluble in the solvent dichloromethane or chloroform and

separation by filtration while the desired product hydrochloride salt remains in solution. The desired intermediate is then isolated as the free base and purified by removal of solvent to afford the intermediate (III) with a purity of 99.7% by HPLC. Although control of the isomeric purity was somewhat achieved by this method, the loss of significant quantities of the desired product (III) could not be avoided and this route is not attractive for commercial production, particularly as the process involved the use of several solvents and lengthy process for separation of undesired isomer which makes the process less feasible for scale-up. In addition, regioisomeric impurity (V) could still be detected in the product (III) and, as described above, this is a great disadvantage in the preparation of Letrozole as impurity (V) is converted into regioisomeric impurity (II) which is very difficult to remove from Letrozole on a commercial scale.
A regiospecific preparation of intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III), was disclosed in patent application WO 2004/076409. The disclosed process afforded intermediate (III) significantly free from its regioisomeric impurity by using the 4-amino-derivative of 1,2,4-triazole so that regioselectivity in the reaction can be achieved. The desired intermediate 4-[{1-(1, 2,4-triazolyl)methyl]benzonitrile (III) was obtained by de-amination of its 4-amino derivative with sodium nitrite and concentrated hydrochloric acid. However, this process suffers from the disadvantages that extra steps are involved in the synthesis and toxic nitrous acid is formed during the de-amination reaction. Consequently, it is not a very safe and feasible approach for the commercial production of Letrozole. In addition, this process, although reducing the level of 1,3,4-triazolyl isomeric impurity, did not totally eliminate the formation of the impurity.
Similar approaches to reducing the regioisomeric impurity were discussed in patent applications WO 2007/039912 and US 2007/0066831, wherein the reaction of an alkali (preferably sodium or potassium) salt of 1,2,4-triazole with a-bromotolunitrile (4-bromomethylbenzonitrile) was disclosed. The alkali salt of 1,2,4-triazole was dissolved in a solvent such as NMP, DMAc, DMF, THF or their mixture and

subsequently treated with 4-bromomethylbenzonitrile to afford intermediate (ill). This process, although reducing the level of 1,3,4-triazolyl isomeric impurity, did not totally eliminate the formation of the impurity. In addition, the formation of the alkali salt of 1,2,4-triazole also increases the time cycle of the process due to the additional step. The process which also required column chromatography for purification of final product Letrozole, which again makes this process is not feasible for industrial application.

(T)
In another approach, disclosed in patent application, WO 2007/144896, a 4,4'-disubstituted diphenylmethane moiety was prepared and then the 1,2,4-triazole ring was introduced to afford Letrozole. The process involved coupling of 4-fluorobenzonitrile (IV) with 4-tolunitrile in DMF using potassium tertiary butoxide as a catalyst. The resulting 4,4-dicyanophenylmethane was brominated with N-bromosuccinimide to afford a bromomethyl intermediate, which was reacted with 1,2,4-triazole to afford Letrozole. However, formation of 1,3,4-triazolyl isomeric impurity (II) could not be totally avoided and, in addition, the reaction of 4-tolunitrile and 4-fluorobenzonitrile also leads to significant formation of tris-phenyl impurity (T) which is problematic to remove, particularly on commercial scale.
Another process, disclosed in patent application, US 2005/0209294, describes the reaction of 4-bromomethylbenzonitrile with the Li, Na or K salt of 1,2,4-triazole in tetrahydrofuran or N,N-dimethylformamide at 10°C. The product, intermediate (111), was then purified by solvent crystallization using a solvent selected from a group comprising 2-propanol, toluene or diisopropyl ether. This process required one

additional step of preparation of 1,2,4-triazole Li, Na or K salt and did not give a pure product.
A further process, disclosed in patent application WO2007/090464 A1, describes the preparation of the intermediate (III) by reacting 1,2,4-triazole with a suspension of sodium hydride before further reaction with 4-bromomethylbenzonitrile. The reaction product was directly converted to Letrozole without further purification. Repetition of the process disclosed in this patent application gave inconsistent regioisomeric impurity levels in Letrozole and intermediate (III) at around 90.0% purity at best. In addition, the use of sodium hydride also makes the process relatively unsafe on a commercial scale.
A process, disclosed in patent application WO 2007/054964 A2, describes the isolation of intermediate (III) by reacting 1,2,4-triazole with 4-bromomethylbenzonitrile in 2-propanol using potassium carbonate as base. After completion of the reaction, the undesired regioisomer (V) was removed by making the hydrochloride salt of the crude reaction mixture followed by solvent extraction and then extracting the product under alkaline condition. Different extractions under various pH conditions to achieve desired purity make the process lengthy and cumbersome and repetition of the process does not lead to intermediate (III) or Letrozole (I) free from their respective regioisomeric impurities.
A process, disclosed in patent application WO2007/107733 A1, includes the use of Cesium carbonate as a base and potassium iodide in catalytic quantity in the reaction of 1,2,4-triazole with 4-bromomethylbenzonitrile. In the reaction, CsC03, Kl and 1,2,4-triazole were taken in acetone and a solution of 4-bromomethylbenzonitrile in DCM was slowly added followed by refluxing of the reaction mixture. Isolation and purification of the desired isomer (III) was carried out by making the hydrochloride salt to afford product (III) in 99% of desired isomeric purity.

Another process, disclosed in patent application, WO 2009/069140 A1, describes the preparation of triazole intermediate (III) by addition of 1,2,4-triazole in small lots to a mixture of 4-bromomethylbenzonitrile and a base (such as sodium and potassium carbonate) in toluene at 50 to 110°C. The residue left after removal of the organic solvent was dissolved in ethyl acetate and washed with water and IPA-HCI solution was added to adjust the pH to between 0 and 2. The purified triazole intermediate was liberated by basifying the hydrochloride salt to afford a product with 99.0% isomeric purity.
In all the acid/base purification methods discussed above, when repeated the regioisomeric purity of desired isomer (ill) or (I) was found to be 99.0% at best. The methods also required extraction with various solvents and/or column chromatography which makes the process less viable for commercial scale.
Therefore the prior art processes described above for the preparation of Letrozole and its intermediates have major disadvantages with respect to the formation and removal of process related impurities; poor commercial viability due to use of hazardous reactants; expensive, time consuming separation methods such as column chromatography and/or low yields of final product.
As the commercial production of Letrozole is of great importance and in view of the above disadvantages associated with the prior art there is a real need for alternative and improved processes for the preparation of Letrozole (I) and intermediate 4-[(1-(1,2,4-triazolyl)-methy[]benzonitrile (III) which do not involve multiple steps and further eliminate the need for cumbersome purification techniques, particularly for the removal of the regioisomers (II) and (V). The alternative processes must be economical and high yielding and provide Letrozole with a high degree of chemical purity.

The present process discloses a simple, economic and commercially viable process for preparation of intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) and Letrozole (I) with 99.7% or more isomeric and chemical purity.
Summary of the Invention
The difficulties encountered in the prior art for preparation of highly pure Letrozole have been successfully overcome in the present invention by preparation of highly pure intermediate intermediate 4-[{1-{1,2,4-triazolyl)methyl]benzonitrile (III) via its salt.
Therefore a first aspect of the present invention provides either an acid addition salt of 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) wherein the acid is not hydrochloric acid or an acid addition salt of 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) wherein the acid is an organic acid. Preferably, the acid is a carboxylic acid, such as a mono-, a di- or a tri-carboxylic acid. Preferably, the mono-carboxylic acid is selected from formic acid, acetic acid, propionic acid or butyric acid. Preferabiy.the di-carboxy!ic acid is selected from oxalic acid, tartaric acid, succinic acid or fumaric acid, more preferably, oxalic acid. Alternatively, the acid is an organic sulfonic acid, preferably selected from methane sulfonic acid, benzene sulfonic acid or p-toluenesulfonic acid.
A second aspect of the present invention provides a process for the preparation of a salt according to the first aspect of the present invention comprising mixing 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) with the acid in a solvent system. Preferably, the solvent system comprises one or more solvents selected from straight chain or branched aliphatic ketones and aliphatic Ci to C4 alcohols or mixtures thereof. Preferably the ketone is selected from acetone, methyl ethyl ketone and methyl isopropyl ketone or mixtures thereof. Preferably, the alcohol is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and tertiary butanol or mixtures thereof. Most preferably, the solvent system comprises acetone and methanol and preferably the ratio of acetone.methanol in the solvent mixture is 95:5, more preferably 80:20, more preferably 60:40 and most preferably 50:50. Preferably the

acid is reacted with 4-[{1-(!2,4-triazolyl)methyl]benzonitrile (III) at a temperature of 10 to 60°C, more preferably at 20 to 40°C and most preferably at 25 to 30°C.
A third aspect of the present invention provides a process for the preparation of 4-[(1-(1,2,4-triazolyl)methyi]benzonitrile (III) comprising the reaction of 4-bromomethylbenzonitrile with 1,2,4-triazole in the presence of a base and a catalytic quantity of iodide ion in a solvent system._PreferabIy, the solvent system comprises one or more solvents selected from straight chain or branched aliphatic ketones and aliphatic Ci to C* alcohols or mixtures thereof. Preferably, the ketone is selected from acetone, methyl ethyl ketone and methyl isopropyl ketone or mixtures thereof. Preferably, the alcohol is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and tertiary butanol or mixtures thereof. Preferably, the solvent system comprises acetone and methanol. Preferably, the ratio of acetone:methanol in the solvent mixture is 95:5, more preferably 80:20, more preferably 60:40 and most preferably 50:50. Preferably the 4-bromomethylbenzonitrile is reacted with 1,2,4-triazole at a temperature of 20 to 100°C, more preferably at 20 to 60°C, more preferably at 20 to 40°C and most preferably at 25 to 30°C. Preferably, the base is a metal carbonate, preferably potassium carbonate or sodium carbonate. Preferably, the iodide ion is present as potassium iodide or sodium iodide. Preferably, the 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) formed is converted to a salt according to a process of the second aspect of the present invention
A fourth aspect of the present invention provides a process for the preparation of 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) comprising purification of the salt according to the first aspect of the present invention, or a salt prepared by a process according to an aspect of the present inevntion, and subsequent liberation of 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) from the purified salt. Preferably, the salt is purified by crystallisation from a solvent system. Preferably, the solvent system comprises one or more solvents selected from straight chain or branched aliphatic ketones and aliphatic Ci to C4 alcohols or mixtures thereof. Preferably, the ketone is selected from acetone, methyl ethyl ketone and methyl isopropyl ketone or mixtures thereof.

Preferably, the alcohol is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and tertiary butanol or mixtures thereof, preferably, the solvent system comprises acetone and methanol. Preferably, the ratio of acetone:methanol in the solvent mixture is 95:5, more preferably 80:20, more preferably 60:40 and most preferably 50:50. Preferably the salt is purified in the solvent system at a temperature of 10 to 60°C, more preferably at 20 to 40°C and most preferably at 25 to 30°C.
Preferably the 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) or the salt thereof which is prepared according to an aspect of the present invention is further converted to Letrozole (I) or a pharmaceutically acceptable salt thereof. Preferably the 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) or the salt thereof which is prepared according to an aspect of the present invention is further converted to Letrozole (I) or a pharmaceutically acceptable salt thereof by reaction with 4-fluorobenzonitrile (IV), preferably at a temperature of -20°C to 0°C, more preferably at a temperature of -20°C to -10°C and most preferably at a temperature of -20°C to -15°C. Optionally, the 4-[{1-(1,2,4-triazolyl)methyl]benzonitrile (III) or the salt thereof is not isolated and used in situ.
A fifth aspect of the present invention provides a process for the preparation of Letrozole (I) or a pharmaceutically acceptable salt thereof, wherein the process uses a salt according to the first aspect of the present invention.
A sixth aspect of the present invention provides 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) or the salt thereof when prepared by a process according to an aspect of the present invention.
A seventh aspect of the present invention provides 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (111) or the salt thereof when prepared by a process according to an aspect of the present invention substantially free of the regioisomeric impurity (V) or the salt thereof.

An eighth aspect of the present invention provides 4-[(1-(1,2,4-triazoIyl)methyl]benzonitrile (III) or the salt thereof substantially free of the regioisomeric impurity (V) or the salt thereof.
A ninth aspect of the present invention provides 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III), with HPLC purity of equal or more than 99.8%, substantially free of the regioisomeric impurity (V).
A tenth aspect of the present invention provides Letrozole when prepared by a process according to an aspect of the present invention.
An eleventh aspect of the present invention provides Letrozole substantially free of the regioisomeric impurity (II).
A twelth aspect of the present invention provides Letrozole, when prepared by a process according to an aspect of the present invention, substantially free of the regioisomeric impurity (II).
A thirteenth aspect of the present invention provides Letrozole, with a HPLC purity equal or more than 99.9%, substantially free of the regioisomeric impurity (II).
A fourteenth aspect of the present invention provides a pharmaceutical composition comprising Letrozole, or a pharmaceutical^ acceptable salt thereof, according to the tenth, eleventh, twelth or thirteenth aspect of the present invention. A fifteenth aspect of the present invention provides the use of a pharmaceutical composition according to the fourteenth aspect present invention in the manufacture of a medicament for the treatment of breast cancer.
A sixteenth aspect of the present invention provides anhydrous crystalline 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III), preferably having an X-ray powder diffraction pattern comprising at least 3 characteristic peaks at about 4.91, 7.60, 8.70,

11.80,12.65, 15.80, 16.74, 17.31, 18.47, 20.13, 21.22, 21.73, 22.88, 23.26, 24.10, 26.01, 28.25 and 29.40 degrees 2 8 ± 0.2, more preferably at least 7 characteristic peaks at about 4.91, 7.60, 8.70, 11.80,12.65, 15.80, 16.74, 17.31, 18.47, 20.13, 21.22, 21.73, 22.88, 23.26, 24.10, 26.01, 28.25 and 29.40 degrees 28 + 0.2. Preferably, the anhydrous crystalline 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (111) is substantially free of regioisomeric impurity (V).
A seventeenth aspect of the present invention provides a process for the preparation of Letrozole (I), or a pharmaceutical^ acceptable salt thereof, wherein the process uses the anhydrous crystalline 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) according to the sixteenth aspect of the present invention as an intermediate.
The term Letrozole as used herein throughout the description and claims means Letrozole and/or any salt, solvate or polymorph thereof, unless otherwise specified.
For the purposes of the present invention, the Letrozole (I) and 4-[(1-(1,2,4-triazolyl)methyl]-benzonitrile (III) and their salts are "substantially free" of chemical or regioisomeric impurities, if they comprise less than 0.3% impurity, preferably less than 0.2%, preferably less than 0.1% and most preferably less than 0.05%.
Brief Description of the Figures
Figure-1: Synthetic scheme for 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile
Figure-2: Synthestic scheme for Letrozole
Figure-3: XRPD of anhydrous crystalline intermediate 4-[(1-(1, 2, 4-
triazolyl)methy]]benzonitrile according to the invention. Figure-4: Differential Scanning Calorimetry of anhydrous crystalline intermediate 4-
[(1-(1,2,4-triazolyl) methyljbenzonitrile according to the invention. Figure-5: Thermogravimetric analysis of anhydrous crystalline intermediate 4-[(1-
(1,2,4-triazolyl) methyljbenzonitrile according to invention.

Equipment detail and conditions used for the testing:
XRPD: Recorded on Bruker D8 Advance diffractometer using a CuKal source.
DSC: Recoded on Perkin Elmer Pyris 6 over a range of 25°C to 250°C at a rate of 10°C/min.
TGA: Thermo Gravimetric analysis (TGA) was carried out on Perkin Elmer Pyris 1
and recorded over a range of 25°C to 250°C at a rate 10°C per minute. No
weight loss was observed.
HPLC: System : Waters E-2695
Detector : W 2489; at wavelength 230nm. Column : L1, C-18 RP column
Detailed Description of the Invention
The inventors have found that Letrozole can be regioselectively synthesized using new processes for the preparation of pure intermediate 4-[(1-(1, 2, 4-triazolyl)methyl]benzonitriIe (III) using novel salts and/or by specific reaction conditions for the preparation of (III). The Letrozole thus obtained is surprisingly substantially free from the regioisomeric impurity (II) and is a major advance over the various processes described in the prior art discussed above.
Therefore, the present invention provides a simple, convenient and inexpensive method for the preparation of highly pure intermediate 4-[(1-(1, 2, 4-triazolyl)methyl]benzonitrile (III), Letrozole and their pharmaceutically acceptable salts. The products obtained from the processes of the present invention are surprisingly very pure without the need for cumbersome purification techniques, such as column chromatography. In particular, the present invention provides Letrozole, 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) and their salts, substantially free of regioisomeric impurities.
The present invention provides a process for the preparation of 4-[(1-(1,2,4-tria2olyl)methyl]- benzonitrile (III) substantially free of its isomeric impurity (V) and Letrozole substantially free of its isomeric impurity (II, Impurity A as mentioned in USP pharmacopoeia specifications).

Preferred aspects of the present invention provide a commercially viable process for preparation of pure intermediate 4-[(1-(1,2,4-triazolyI)methyl]benzonitrile (III) having a chemical purity more than 99.5%, preferably more than 99.6%, preferably more than 99.7%, preferably more than 99.8%, and most preferably more than 99.9%, which is also substantially free of regioisomeric impurity (V).
A particularly preferred process for the preparation of intermediate 4-[(1 -(1,2,4-triazolyl)methyl]benzonitrile (111) is illustrated in Frgure-1.
A particularly preferred aspect of the present invention provides a method for synthesis of an intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (111) comprising one or more of the following steps:
a) Preparing a solution of 4-bromomethylbenzonitrile in polar solvents such as aliphatic alcohols, preferably methanol and a dialkyl ketone, preferably acetone or their mixture, and adding potassium carbonate and potassium iodide
b) Slow addition of 1, 2, 4-triazole dissolved in polar such as aliphatic alcohols, preferably methanol and a dialkyl ketone, preferably acetone or their mixture into the reaction mixture at 20 to 35°C.
c) Stirring of the reaction mixture at 20 to 35°C until completion of the reaction.
d) Filtration of potassium carbonate and potassium iodide and removal of the solvent by distillation.
e) Addition of water to the residue and extraction of the crude 4-[(1-(1,2,4-triazolyl)- methyl]benzonitrile dissolved in aqueous layer with a solvent such as dichloromethane (DCM).
f) Removal of the DCM to afford crude 4-[(1-(1,2,4-triazolyl)methyl] benzon itrile.

g) Preparation of an organic acid salt, preferably the oxalate salt, of crude
4-[(1-{1,2,- 4-triazolyl)methyl]benzonitrile in a poiar solvent such as
methanol or acetone or a mixture of both. h) Liberation of the free base of the oxalate salt by its treatment with an
aqueous solution of a base, such as sodium hydroxide, and isolation of
the liberated base from water by filtration.
i) Dissolving the purified base of the isolated solid in dichloromethane and
removal of insoluble sodium salt of organic acid by filtration.
j) Isolation of the purified 4-[(1-(1l2,4-triazolyl)methyl]benzonitrile as a
white solid by removal of solvent from the filtered dichloromethane layer
and addition of a non-polar solvent, such as a hydrocarbon, preferably
n-heptane.
A particularly preferred process for the preparation of Letrozole (I) is illustrated in Figure-2.
A particularly preferred process for the preparation of Letrozole comprises one or more of the following steps:
(a) Dissolving potassium tertiary butoxide in Dimethylformamide.
(b) Addition of 4-[{1 -(1,2,4-triazolyl)methyl]benzonitrile solution in Dimethylformamide into potassium tertiary butoxide solution in a solvent such as Dimethylformamide, preferably at a temperature of-5 to -15°C.
(c) Mixing with a 4-Fluorobenzonitrle solution in Dimethylformamide, preferably at the same temperature as in step (b).
(d) After completion of the reaction addition of water immiscible solvent such as dichloromethane followed by addition of an organic acid, preferably acetic acid and removal of the potassium acetate by filtration of the reaction mixture.
(e) Washing of the organic layer with water and then removal of solvent.

(f) Dissolving the residue in a polar solvent such as an alcohol, preferably methanol or 2-propanol, and addition of a non-polar solvent such as n-heptane.
(g) Isolation of the solid Letrozole with >99% purity on HPLC.
(h) Purification of Letrozole using a solvent, such as an alkyl ester of alkyl carboxylic acid, such as ethyl acetate, and a non polar solvent, preferably alkanes such as n-heptane or dialkyl ethers such as tert-butylmethy ether to afford pure Letrozole with HPLC purity 99.9% or higher.
In a preferred embodiment the solid obtained in step (h) is dried at a temperature between about 30-60°C, more preferably at 40-60°C and most preferably at 50-55°C under reduced pressure, preferably for approximately 2 to 6 hours.
Various prior art processes described the reaction of 4-bromomethylbenzonitrile with 1,2,4-triazole, with a suitable base and solvent at reflux temperature. The present inventors observed that when the reaction was carried out in methanol or acetone individually, the refluxing was required to complete the reaction however, it has been surprisingly found that using a mixture of solvents such as a ketone and an alcohol (for example acetone and methanol), after an appropriate adjustment of solvent ratio, quantity of base (eg potassium carbonate) and catalyst (eg potassium iodide), the reaction can be completed at ambient temperature i.e. at 20 to 35°C. It was also surprisingly found that the regioselectivity of the reaction was much higher. The unwanted regioisomer (V) was found in less than 12% in the crude product as compared with prior art processes wherein the regioisomer (V) was formed in an amount between 15 to 20% or higher.
Various purification methods such as solvent purification and selective preparations of hydrochloride salts were described in prior art but these methods could not make the intermediate (III) highly pure. The inventors have surprisingly found that the preparation of the salt of the crude 4-[(1-(1,2,4-trrazolyl)methyl]benzonitrile (III) with

relatively weak acids, such as various organic acids like carboxylic acid beside and sulfonic acids like methane sulfonic acid or para-toluene sulfonic acids were used it was observed that very high purity could be achieved. Dicarboxylic acid salts, especially oxalic acid, salt are most preferred for achieving the desired regioisomeric and chemical purity of 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) with good yield.
The processes according to the present invention may be used for the preparation of the organic acid salt intermediates with the following acids: formic acid; acetic acid; propionic acid; butyric acid; tartaric acid; oxalic acid; succinic acid; fumaric acid; methane sulfonic acid and p-toluenesulfonic acid. The most preferred acid is oxalic acid.
Furthermore, the present invention provides a method of preparation of 4-[(1 -(1,2,4-triazoly[)methyl]benzonitrile which have the advantageous combination of features not described previously in the prior art. The main advantages are:
1) Reaction of 4-bromomethylbenzonitrile with 1,2,4-triazole at ambient temperature between 20 to 40°C, preferably between 25 to 35°C.
2) Fast completion of reaction in two to four hours which saves reactor occupancy time and increases productivity.
3) Simple work up of reaction mixture for isolation of the crude 4-[(1-(1,2,4-triazolyl)methyl]-benzonitrile.
4) Purification of crude 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile by salt formation with organic sulfonic acids, organic acids preferably aliphatic, aromatic mono carboxylic or dicarboxylic acids, preferably oxalic acid.
5) Selective separation of 4-[(1-(1,2,4-triazo!yl)methyl]benzonitrile from its corresponding regioisomer 4-[(1-(1,3,4-triazolyl)methyl]benzonitrile by specific choice of solvents, preferably the same as used for the preparation and isolation of the organic acid salt.

6) Hydrolysis of organic acid salt and liberation of purified base by using water as solvent to obtain 4-[(1-(1l2,4-triazolyl)methyl]benzonitrile with high chemical purity and substantially free from regioisomeric impurity.
7) Preparation of intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile in crystalline anhydrous form having at least 3 or seven XRPD peaks at 4.91, 7.60, 8.70, 11.80, 12.65, 15.80, 16.74, 17.31, 18.47, 20.13, 21.22, 21.73, 22.88, 23.26, 24.10, 26.01, 28.25 and 29.40 at 2-Theta scale .
8) Preparation of intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile in crystalline anhydrous form having a single endothermic peak at 77 to 79°C in differential scanning calorimetry (DSC analysis).
9) Use of intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile for preparation of Letrozole having a high chemical purity of 99.9% or higher without having any individual known or unknown impurity higher than 0.1%.
The reagents and solvents illustrated in Figures 1 and 2 are merely illustrative of the present invention and the reaction schemes are not limited by these reagents and solvents. Any suitable alternatives can be used.
The processes of the present invention provide a commercially viable process for the preparation of Letrozole resulting in a greater than 60% molar overall yield and HPLC purity of 99.90% or higher, preferably 99.95% or higher, and more preferably 99.98% or higher.
If required, Letrozole can be prepared from intermediate (III), prepared according to an aspect of the present invention, by its reaction with 4-fluorobenzonitrile (IV) in the presence of strong base like potassium terf-butoxide as described in patent US 4978672 and other prior art process described above.
Preferably, the final purification of Letrozole is carried out by using a solvent mixture having a solvent derived from aliphatic acid ester such as ethyl acetate, isopropyl acetate or amyl acetate and non polar solvents such as ethers, preferably ethyl ether

or tertiary butyl methyl ether (TBME). Preferably, the aliphatic acid ester is ethyl acetate and the ether is tertiary butyl methyl ether (TBME).
Preferably, the Letrozole is prepared having a purity of more than 99.8% with isomeric impurity less than 0.1%.
Preferably, the products are obtained in a yield of 70% or more, preferably 80% or more, preferably 90% or more, preferably 95% or more. Preferably, the Letrozole is obtained substantially free of chemical impurities.
Preferably, the Letrozole is obtained on a commercial scale, preferably in batches of 1kg or more, 10kg or more, 100kg or more, 500kg or more, or 1000kg or more.
The pharmaceutical composition according to the fourteenth aspect of the present invention can be a solution or suspension form but is preferably a solid oral dosage form. Preferred dosage forms in accordance with the invention include tablets, capsules and the like which, optionally, may be coated if desired. Tablets can be prepared by conventional techniques, including direct compression, wet granulation and dry granulation. Capsules are generally formed from a gelatine material and can include a conventionally prepared granulate of excipients in accordance with the invention. The pharmaceutical composition according to the present invention typically comprises one or more conventional pharmaceutically acceptable excipient(s) selected from the group comprising of a filler, a binder, a disintegrant, a lubricant and optionally further comprises at least one excipient selected from colouring agents, adsorbents, surfactants, film formers and plasticizers.
As described above, the pharmaceutical composition of the present invention typically comprises one or more fillers, such as microcrystalline cellulose, lactose, sugars, starches modified starches, mannitol, sorbitol and other polyols, dextrin, dextran or maltodextrin; one or more binders, such as lactose, starches, modified starch, maize starch, dextrin, dextran, maltodextrin, microcrystalline cellulose, sugars,

polyethylene glycols, hydroxy propyl cellulose, hydroxy propyl methylcellulose, ethylcellulose, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, gelatin, acacia gum, tragacanth, polyvinylpyrrolidone or crospovidone; one or more disintegrating agents such as croscarmelllose sodium, cross-linked polyvinylpyrrolidone, crospovidone, cross-linked carboxymethyl starch, starches, microcrystalline cellulose, polyacrylin potassium, one or more different glidants or lubricants such as magnesium stearate, calcium stearate, zinc stearate, calcium behenate, sodium stearyl fumarate, talc, magnesium trisilicate, stearic acid, palmitic acid, carnauba wax or silicon dioxide.
If required, the pharmaceutical composition of the present invention may also include surfactants and other conventional excipients.
If the solid pharmaceutical formulation is in the form of coated tablets, the coating may be prepared from at least one film-former such as hydroxypropyl methylcellulose, hydroxypropyl cellulose or methacrylate polymers which optionally may contain at least from one plasticizer such as polyethylene glycols, dibutyl sebacate, triethyl citrate, and other pharmaceutical auxiliary substances conventional for film coatings, such as pigments, fillers and others.
A fifteenth aspect of the present invention provides the use of a pharmaceutical composition according to the fourteenth aspect of the present invention in the manufacture of a medicament for the treatment of cancer, in particular for the treatment of breast cancer in post menopausal women.
The details of the invention, its objects and advantages are explained hereunder in greater detail in the following non-limiting examples.

EXAMPLES
Example 1
4-[(1-(1,2,4-triazolyl)methyl]benzonitrile(lll)
Potassium carbonate (70g, 0.507 mole) and potassium iodide <8.4g, 0.051 mole) were added to a solution of 4-bromomethylbenzonitrile (100g, 0.510 mole) in acetone (500 ml.). To this reaction mixture, a solution of 1,2,4-triazole (35g, 0.507 mole) in methanol (500ml) was slowly added under nitrogen at 25 to 35°C over a period of 1 hour. The reaction mixture was stirred for a further two to four hours and, after completion of the reaction, the solid was filtered and the filtrate was concentrated by distillation at 40 to 45°C under reduced pressure. Water (2000 ml.) was added to the residue and the pH of reaction mixture was adjusted in between 6 to 7 with acetic acid (3 to 4 ml.). The aqueous layer was extracted with dichloromethane (2000 ml.) and the organic extract was washed with water (200 ml.) and the organic solvent was removed by distillation at 40 to 45CC under reduced pressure to afford 4-[(1-(1,2,4-triazolyl)methyl]-benzonitrile (III) as a crude residue.
A solution of oxalic acid (68g, 0.540 moles) in an equal volume (50:50) mixture of acetone and methanol (300ml.) was prepared and added to a solution of the crude residue in an equal volume (50:50) mixture of acetone and methanol (100 ml.) under stirring at 25-30°C. After stirring for a further 30 minutes, the reaction mixture was cooled at 10 to 15°C and then filtered to afford the oxalate salt of 4-[(1-(1,2,4-triazolyl)methyl]-benzonitrile and the solid was washed with equal volume mixture of acetone and methanol (50 ml.) and dried under suction.
The solid oxalate salt obtained was suspended in water and its pH was made alkaline (pH 7 to 8) by slow addition of a sodium hydroxide solution (10% w/V, ~200 ml.) under stirring. The reaction mass was cooled at 10 to 15°C, filtered and the isolated solid was washed with water and sucked dry. The isolated solid was then dissolved in dichloromethane and insoluble sodium oxalate was removed by filtration. The clear solution was concentrated until approximately 90% was removed and n-heptane (120 ml) was added to the residue under stirring. The solid obtained was filtered and dried

under suction. The product was dried at 45 to 50° C at reduced pressure to afford 4-
[(1-(1,2,4-triazolyl)methyl]-benzonitrile (III) as a pure, off-white, free flowing solid.
The product is characterised as the novel anhydrous crystalline 4-[(1-(1,2,4-
triazolyl)methyl]benzonitrile (III) with XRPD as in Figure-3, DSC as in Figure-4 and
TGA as in Figure-5.
Yield: 45.5 g. (48.5% molar from 4-bromomethylbenzonitrile)
HPLC Purity: 99.8%. The regioisomerrc impurity (V) was present at less than 0.10%
(by area normalization).
Example 2 Letrozole (I)
A solution of the pure 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (100g. 0.543 mole), obtained in Example 1, in N,N-dimethy[formamide (200 ml) was slowly added to a solution of potassium tertiary butoxide (182.9 g, 1.63mole) in N,N-dimethylformamide (400 ml.) under a nitrogen atmosphere whilst the temperature was maintained at -15 to -20°C. After 30 minutes stirring, a solution of 4-fluorobenzonitrile (IV) (65.8g, 0.543 mole) in N,N-dirnethylformamide (50 ml.) was slowly added at the same temperature and the reaction mixture was stirred until completion of the reaction. Acetic acid (200 ml.) was then added to the mixture at -10 to -15°C and the pH of the mixture was adjusted to between about 5 to 6. After stirring for 1 hour, dichloromethane (1500 ml.) was added to the mixture and the resultant mixture was filtered to remove impurities such as potassium acetate.
The clear filtrate was washed with water five times (total 5000 ml.) and then concentrated under reduced pressure. Methanol (200 ml.) was added to the residual semi solid mass, followed by n-heptane (500ml.). The mixture was stirred first at 20 to 25°C followed by cooling to 10-15°C. The isolated sold was filtered and dried under suction. The solid was dissolved in ethyl acetate (1500 ml) by heating and the clear solution was filtered and concentrated to 500 ml by distillation under reduced pressure. Te/f-butyl methyl ether (TBME, 500 ml.) was added to this residual solution and the mixture was cooled at 10 to 15°C. The precipitated solid was filtered, washed

with TBME and dried under suction before being dried in a vacuum drier at 50 to 55"C under low pressure to afford pure Letrozole (I) as a white to off-white solid. Yield: 95 g. (62% molar)
HPLC purity: 99.9% (by area normalization). The regioisomeric impurity (II) could not be detected.

Claims
1. An acid addition salt of 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) wherein the acid is not hydrochloric acid.
2. An acid addition salt of 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) wherein the acid is an organic acid
3. A salt according to claims 1 or 2 wherein the acid is a carboxylic acid.
4. A salt according to claim 3 wherein the carboxylic acid is a mono-, a di- or a tri-carboxylic acid.
5. A salt according to claim 4 wherein the mono-carboxylic acid is selected from formic acid, acetic acid, propionic acid or butyric acid.
6. A salt according to claim 4 wherein the di-carboxylic acid is selected from oxalic acid, tartaric acid, succinic acid or fumaric acid.
7. A salt according to claim 6 wherein the acid is oxalic acid.
8. A salt according to claims 1 or 2 wherein the acid is an organic sulfonic acid.
9. A salt according to claim 8 wherein the acid is selected from methane sulfonic acid, benzene sulfonic acid or p-toluenesulfonic acid.
10. A process for the preparation of a salt according to claims 1 to 9 comprising mixing 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) with the acid in a solvent system.
11. A process according to claim 10 wherein the solvent system comprises one or more solvents selected from straight chain or branched aliphatic ketones and aliphatic C1 to C4 alcohols or mixtures thereof.
12. A process according to claim 11 wherein the ketone is selected from acetone, methyl ethyl ketone and methyl isopropyl ketone or mixtures thereof.
13. A process according to claim 11 wherein the alcohol is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and tertiary butanol or mixtures thereof.
14. A process according to claim 11 wherein the solvent system comprises acetone and methanol.

15. A process according to claim 14 wherein the ratio of acetone:methanol in the solvent mixture is 95:5,
16. A process according to claim 15 wherein the ratio of acetone:methanol in the solvent mixture is 80:20 ,
17. A process according to claim 16 wherein the ratio of acetone:methanol in the solvent mixture is 60:40.
18. A process according to claim 17 wherein the ratio of acetone:methanol in the solvent mixture is 50:50.
19. A process for the preparation of 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) comprising reaction of 4-bromomethylbenzonitrile with 1,2,4-triazole in the presence of a base and a catalytic quantity of iodide ion in a solvent system.
20. A process according to claim 19 wherein the solvent system comprises one or more solvents selected from straight chain or branched aliphatic ketones and aliphatic C1 to C4 alcohols or mixtures thereof.
21. A process according to claim 20 wherein the ketone is selected from acetone, methyl ethyl ketone and methyl isopropyl ketone or mixtures thereof.
22. A process according to claim 21 wherein the alcohol is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and tertiary butanol or mixtures thereof.
23. A process according to claim 20 wherein the solvent comprises acetone and methanol.
24. A process according to claim 23 wherein the ratio of acetone:methanol in the solvent mixture is 95:5,
25. A process according to claim 24 wherein the ratio of acetone:methanol in the solvent mixture is 80:20 ,
26. A process according to claim 25 wherein the ratio of acetone:methanol in the solvent mixture is 60:40.
27. A process according to claim 26 wherein the ratio of acetone:methanol in the solvent mixture is 50:50.
28. A process according to any of claims 19 to 27 where the base is a metal carbonate.

29. A process according to claim 28 where the base is potassium carbonate or sodium carbonate.
30. A process according to any of claims 19 to 29 where the iodide ion is present as potassium iodide or sodium iodide.
31. A process according to claims 19 to 30 wherein the 4-[(1-(1,2,4-triazolyl) methyl] benzonitrile (III) formed is converted to a salt according to the processes of any one of claims 10 to 18.
32. A process for the preparation of 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) comprising purification of a salt according to claims 1 to 9, or a salt prepared by a process according one of claims 10 to 18 or 31, and subsequent liberation of 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) from the purified salt.
33. A process according to claim 32 wherein the salt is purified by crystallisation from a solvent system.
34. A process according to claim 33 wherein the solvent system is selected from solvent systems as defined in claims 11 to 18.
35. A process according to any one of claims 10 to 34 wherein the 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) or the salt thereof which is prepared is further converted to Letrozole (I) or a pharmaceutically acceptable salt thereof.
36. A process according to claim 35 wherein the 4-[(1-(1,2,4-triazoly!)methyl]benzonitrile (III) or the salt thereof is not isolated and used in situ.
37. A process for the preparation of Letrozole (I) or a pharmaceutically acceptable salt thereof, wherein the process uses a salt according to claims 1 to 9 as an intermediate.
38.4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) or the salt thereof when prepared
by a process according to claims 10 to 31.
39.4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) or the salt thereof when prepared
by a process according to claims 10 to 31 substantially free of the
regioisomeric impurity (V) or the salt thereof. 40.4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) or the salt thereof substantially
free of the regioisomeric impurity (V) or the salt thereof.

41.4-[(1-(1,2,4-triazolyl)methylJbenzonitrile (III), with HPLC purity of equal or more than 99.8%, substantially free of the regioisomeric impurity (V).
42. Letrozole when prepared by a process according to claims 35 to 37.
43. Letrozole substantially free of the regioisomeric impurity (II).
44. Letrozole, when prepared by a process according to claims 35 to 37, substantially free of the regioisomeric impurity (II).
45. Letrozole, with HPLC purity equal or more than 99.9%, substantially free of the regioisomeric impurity (II).
46. A pharmaceutical composition comprising Letrozole, or a pharmaceutically acceptable salt thereof, according to claims 42 to 45.
47. The use of a pharmaceutical composition according to claim 46 in the manufacture of a medicament for the treatment of breast cancer.
48. Anhydrous crystalline 4-[(1-(1,2l4-triazolyl)methyl]benzonitrile (III).
49. Anhydrous crystalline 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) according to claim 48 having an X-ray powder diffraction pattern comprising at least 3 characteristic peaks at about 4.91, 7.60, 8.70, 11.80,12.65, 15.80, 16.74, 17.31, 18.47, 20.13, 21.22, 21.73, 22.88, 23.26, 24.10, 26.01, 28.25 and 29.40 degrees 2 9 ± 0.2.
50. Anhydrous crystalline 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) according to claim 49 having an X-ray powder diffraction pattern comprising at least 7 characteristic peaks at about 4.91, 7.60, 8.70, 11.80,12.65, 15.80, 16.74, 17.31, 18.47, 20.13, 21.22, 21.73, 22.88, 23.26, 24.10, 26.01, 28.25 and 29.40 degrees 2 6 ± 0.2.
51. Anhydrous crystalline 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) according to claim 48 to 50 substantially free of regioisomeric impurity (V).

52. A process for the preparation of Letrozole (I), or a pharmaceutically acceptable salt thereof, wherein the process uses the anhydrous crystalline 4-[(1-(1, 2, 4-triazolyl) methyl]benzonitrile (III) according to claims 48 to 51 as an
intermediate.