A novel and convenient method of manufacture of Letrozole
Field of the invention:
The present invention relates to a novel method of synthesizing ‘Letrozole’ which is a popular antineoplastic aromatase inhibitor and widely used in the treatment of postmenopausal breast cancer.
‘Letrozole’ is chemically represented as 4-[l-(4-Cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl)] benzonitrile.

Background of the invention:
European patent No.: EP 0236940 and the United States patent Nos.: US 4978672, US 5473078 and US 5352795 disclose a method of synthesizing Letrozole (I) by the reaction of 4-Bromomethyl benzonitrile (II) with 1,2,4-triazole to yield 4-[l-(l,2,4-triazol-l-yl)methyl) benzonitrile. (Ilia) which is then reacted with 4-Fluorobenzonitrile to get Letrozole (I) (Scheme-1)


According to the process shown in Scheme-1 the reaction of refluxing alpha-bromo-4-tolunitrile of the formula (II) with 1,2,4-triazole, potassium carbonate in the presence of acetone gives an isomeric mixture of 4-[l-(l,2,4-triazolyl)methyl] benzonitrile of the formula [III(a)] and 4-[l- (l,3,4-triazolyl)methyl]benzonitrile of the formula [III(b)] in 87:11 ratio along with 2% other impurities .This composition of the product mixture is not disclosed in the above mentioned patents, but the indicated ratio is based on our experimental observation. The desired product of the formula III (a) is separated from the impurities using column chromatography technique The column chromatography technique of the purification of the compound of the formula III(a) suffers from the following set backs.
i. Special equipment [ columns] is to be designed in the plant.
ii. Column chromatography technique is not adaptable for multi kilograms level manufacture
iii. It is very time consuming, as it requires slow elution for efficient separation, iv. It involves huge volumes of solvents, which can harm the environment.

v. Solvents recovery is an important task, as inefficient solvent recovery effects the product costing considerably,
vi. Large quantity of chromatography grade adsorbant is required which effects the economy of the process,
vii. Specially trained personnel are required to perform column chromatography technique on a manufacturing scale in the plant.
The above factors render the chromatography technique of purification of the compound of the formula III (a) is unwieldy and unviable for the adaptation of the process on a commercial scale
A second method is also disclosed in the above patents, which consists of treating N- (t)-Bu-4-bromobenzamide (IV) with ethyl formate and butyl lithium. The resulting intermediate is converted to the chloro derivative (V) with thionyl chloride condensation of which with 1,2,4-triazole in Dimethyl formamide (DMF) at reflux temperature affords Letrozole (Scheme-2)
(Scheme-2):


The second method (Scheme-2) suffers from the following drawbacks
1. It involves use of hygroscopic and pyrophoric organometallic reagents like butyl lithium, which is extremely hazardous and beset with handling problems on scaleup.
2. Further Butyl lithium solution is used in huge volumes. As this reagent is highly expensive it effects economy of the process.
3. Temperatures of the order of -60°C have to be employed which is also not viable from the manufacturing viewpoint.
4. Quenching with Ammonium chloride solution is highly exothermic.
5. Also, quenching at -60°C results is hard solid mass, which is not stirrable, and posess problem in scale-up reactions.
6. Yields are not reported for any of the stages however realized yield for stage-I is very less i.e., about 25%, thus rendering overall yield very poor.
7. Further the process reported for the final stage i.e., to form letrozole of formula I by heating compound of formula V with 1,2,4-triazole in refluxing DMF is not reproducible.
Both the prior-Art processes available in literature are highly unsatisfactory for industrial
application as discussed above
It is very important to examine a process of preparing the compound of the formula (VII) from the point of industrial applicability whether the procedure fulfills the following requirements Therefore we directed our R & D program to develop an improved process for the preparation of letrozole of the formula I taking into consideration the following requirements.
1. The starting materials for the process should be easily available and cheap for commercial scale operations
2. The use of harmful reagents should be avoided.
3. The process should be safe from the point of environmental protection
4. The formation of by-products and ballast materials, which cannot be used or processed, further, should be minimized during the course of the process.
5. The process mentioned should be reproducible and adaptable for industrial scale operations.
6. It is also very important, that the process should result in the formation of pure final product, which does not need further expensive purification.

Therefore we directed our R & D program to develop an improved process for the preparation of letrozole of the formula I taking into consideration the following requirements.
Objective and summary of the present invention:
Based on the above requirements we directed our research focusing on the following objectives
• Avoiding the usage of Butyl lithium and other hazardous reagents.
• Avoiding column-chromatography
• Reducing number of stages
• Improving the over all yield of the final product.
• Achieving a high purity for the final product i.e., not less than 99.8%
Accordingly, we developed a novel process for manufacture of Letrozole meeting our objectives and consisting of the following steps:
• Treating 4-Tolunitrile with 4-Fluorbenzonitrile in presence of potassium- (t)-butoxide to get 4,4’-Dicyanodiphenyl methane (VI) by a novel process.
• Brominating compound of formula (VI) with N-Bromosuccinimide to ge 4-(oc-Bromo-4-cyanobenzyl) benzonitrile (VII) by a novel process
• Condensing the intermediate 4-(a-Bromo-4-cyanobenzyl)benzonitrile (VII) with 1,2,4-
Triazole to yield letrozole of formula I
The main objective of the present invention is to provide an improved process for the preparation of letrozole of formula (I) avoiding the drawbacks of the hitherto known
processes.
Another objective of the present invention is to provide a novel process for the intermediate of the formula VI useful for the preparation of the compound of the formula I
Another objective of the present invention is to provide an improved process for the preparation of letrozole of formula (I) avoiding the usage of butyl lithium

Yet another objective of the present invention is to provide an improved process for the preparation of letrozole of formula (I) avoiding the usage of column chromatography.
Still another objective of the present invention is to provide an improved process for the preparation of letrozole of formula (I) avoiding low temperatures of the order of -60°C
Yet another objective of the present invention is to provide an improved process for the preparation of letrozole of formula (I) by reducing the number of purification steps
Still another objective of the present invention is to provide an improved process for the preparation of letrozole of formula (VII) in which the over all yield is improved
Yet another objective of the present invention is to provide an improved process for the preparation of letrozole of formula (I) in which high purity is achieved for the final product.
Yet another objective of the present invention is to brominate the compound of the formula VI to yield 4-(ct-Bromo-4-cyanobenzyl)benzonitrile (VII) and isolate it in pure state
Still another objective of the present invention is to condense 4-(oc-Bromo-4-cyanobenzyl)benzonitrile (VII) with 1,2,4-triazole to get Letrozole of the formula(I)
Thus a novel method of synthesis for Letrozole (I) is developed as depicted in the reaction Scheme-3.

According to the present invention
1. 4-Tolunitrile is treated with 4-Fluorobenzonitrile in presence of potassium- (t)-butoxide to get 4,4’-Dicyanodiphenyl methane (VI) as an intermediate in 30-40% yield.
2. The 4?4’-Dicyanodiphenyl methane (VI) is brominated with N-Bromosuccinimide in chloroform medium to get 4-(ot-Bromo-4-cyanobenzyl) benzonitrile (VII) which is crystallized from ethyl acetate/hexane in 60-65% yield.

3. The intermediate 4-(a-Bromo-4-cyanobenzyl)benzonitrile (VII) is condensed with 1,2,4- triazole in Isopropanol(IPA) medium to get Letrozole (I) in 50-55% yield. Letrozole (I) thus obtained is about 95% pure
4. Crystallization of the letrozole of the formula (I) with methanol to get pharmaceutical grade product of 99.8% purity.
The amount of 4-Fluorobenzonitrile used in step (1) may be in the range of l-1.5moles,
preferably 1.1 moles. The amount of potassium- (t)-butoxide may be in the range of 2-2.5 moles preferably 2.1 moles.
The amount of N-Bromosuccinimide used in step (2) may be in the range of l-1.5moles preferably 1.2 moles.
The amount of 1,2,4-triazole used in step (3) may be in the range of 3-5 moles, preferably 4 moles.
The details of the inventions are given in the Examples given below which are provided for illustration only and therefore these examples should not be construed to limit the scope of the invention.

Examples
(a) Preparation of the 4,4’-DicvanodipheriYl methane of the formula (VI):
To a solution of 1.8 Kg of potassium- (t)-butoxide in 5.4 Lts of DMF at -10°C, is added a mixture of 1.0 of p-tolunitrile and 1.14 kg of p-Fluorobenzonitrile during 2-3 hours. The mixture is maintained at the same temperature for 2 hrs and quenched into saturated ammonium chloride solution. The reaction mixture is extracted with chloroform; the organic phase is separated, washed with brine, dried over sodium sulphate and evaporated. The resulting crystalline product is filtered after trituration with Isopropyl ether (yield: 0.65 Kgs) melting point: 168.3°C, purity by HPLC: 99.9%
(b) Preparation of 4-(a-Bromo-4-cyanobenzYD benzonitrile of the formula (VIP:
To a solution of 0.65 kgs of 4,4’-Dicyanodiphenyl methane of formula (VI) in 10L of chloroform are added 0.53 kgs of N-bromo succinimide and 8 gms of benzoyl peroxide sequentially. The reaction mixture is heated to reflux temperature and maintained at the same temperature for 9-10 hrs. The reaction mixture is poured into 3.5 L of water and extracted with chloroform. The chloroform extract is water washed, dried over sodium sulphate and evaporated. To the residue a mixture of 2L of ethyl acetate and 1.3 L of hexane is added and stirred for 1 hr at room temperature. The resulting solid is filtered to yield 0.54 kgs of compound of formula (VII) melting point: 120.8°C, purity by HPLC: 96%
(c) Preparation of letrozole of the formula (I):
To a solution of 0.54 kg of 4-(a-Bromo-4-cyanobenzyl) benzonitrile of the formula (VII) in 10L of Isopropanol are charged 0.502 kgs of 1,2,4-Triazole, 0.250 kgs of potassium carbonate and 58 gms of tetra butyl ammonium bromide. The reaction mixture is heated to reflux temperature and maintained at the same temperature for 8-9 hrs. The reaction mass is distilled to a residual volume of 2.5 L, cooled to room temperature, filtered and washed with water. Thus obtained crude letrozole is recrystallized twice with methanol to yield 252 gms of pure letrozole. Melting point: 186.3°C; purity by HPLC: 99.94%

(d) Preparation of letrozole of the formula (I):
To a solution of 0.410 kg of 4-(a-Bromo-4-cyanobenzyl) benzonitrile of the formula (VII) in 8L of Isopropanol are charged 0.381 kgs of 1,2,4-Triazole, 0.191 kgs of potassium carbonate and The reaction mixture is heated to reflux temperature and maintained at the same temperature for 8-9 hrs. The reaction mass is distilled to a residual volume of 2.0 L, cooled to room temperature, filtered and washed with water. Thus obtained crude letrozole is recrystallized twice with methanol to yield 180 gins of pure letrozole. Melting point: 186.1 °C; purity by HPLC: 99.92%
Advantages of the present invention:
1) The present invention describes a method of preparing Letrozole employing convenient reaction conditions avoiding hazardous and pyrophoric reagents like butyl lithium.
2) The method disclosed in the current invention employs convenient operating temperatures and avoids the use of temperatures like -60°C, which is difficult to maintain on a manufacturing scale.
3) The method disclosed according to the present invention avoids the formation of large amounts of unwanted side products and the final product can be easily purified to pharmaceutical grade.
4) The method of preparation of the intermediate 4,4’-Dicyanodiphenyl methane (VI) is novel and can be prepared from easily available raw materials in good yields. This intermediate is converted to Letrozole (I) in two steps and this conversion also is novel and is easy to adapt on manufacturing scale.