A novel process for the synthesis of substantially pure Letrozole

This article demonstrates an improved novel and practical synthesis of oral non-steroidal aromatase inhibitor (AI) Letrozole in a five-stage synthetic process in excellent yields. Key steps of the synthesis involve the condensation of 4-(chloro(4-cyanophenyl)methyl)benzamide with 1 H-1,2,4-triazole and further its dehydration to Letrozole by using trifluoroacetic anhydride at low temperature


Introduction
Letrozole 1 (Trade name: Femara) is an antineoplastic agent invented by Novartis Pharmaceuticals Corporation and is used for the treatment of certain types of breast cancer (such as hormone-receptorpositive breast cancer) in women. 1 Letrozole is also used for the slow or reverse growth of breast cancer in women by decreasing the production of estrogen in breast cancer patients. 2,3everal reports are available in the literature for the synthesis of Letrozole 1.Most of these synthetic protocols commenced with 4-((1H-1,2,4-triazol-1-yl)methyl)benzonitrile 6 as a key intermediate, which was further converted into letrozole by reaction with 4-halocyanobenzene 7. [4][5][6][7][8] The nucleophilic substitution on 4,4'-methylene-bis-benzonitrile 3 containing good leaving group at methylene bridge with triazole 4 is also reportedly provided letrozole in excellent yields. 9,10Other notable synthesis of letrozole include the late stage palladium catalysed cyanation on 1-[bis(4-bromophenyl)methyl]-1H-1,2,4-triazole 5 with Zn(CN) 2 . 11onstruction of 1H-1,2,4-triazole ring starting from 4,4'-(hydrazonomethylene)dibenzonitrile, removal of amino functionality by diazotization reaction on amino substituted letrozole, 12 late-stage dehydration of bisoxime 2 to biscyano functionality 13 (Scheme 1) are the other noticeable protocol adapted for the synthesis of letrozole.Considering the high demand and commercial value of letrozole 1 as a drug substance in oncology treatment, despite all these known synthetic procedures, search for an innovative and cost-effective protocol for the synthesis of Letrozole 1 is always in demand.Here in we report an improved alternate synthesis of Letrozole 1 in excellent yields, and this synthetic route has the freedom to operate from the existing patent landscape.
Scheme 1. Various synthetic routes for the synthesis of Letrozole 1.

Scheme 2. Retrosynthetic analysis of Letrozole 1.
During the synthesis of Letrozole 1, initial attempts were focused on the preparation of 4-((4cyanophenyl)(hydroxy)methyl)benzamide 15.Compound 15 was prepared from 4-(4-cyanobenzoyl)benzamide 14 by reduction of keto functionality 14 with sodium borohydride in an alcoholic solvent (Scheme 3).The 4-(4-(cyanobenzoyl)benzamide 14 in turn prepared from 4,4-dibromo benzophenone 13 by cyanation with potassium ferrocyanidetrihydrate in presence of palladium(II)chloride followed by the selective hydrolysis of the cyano group to amide functionality at 100 °C under aerial oxidation in 86% of yield.Tosylation 21 of 4-((4cyanophenyl)(hydroxy)methyl)benzamide 15 was attempted under various conditions using p-toluenesulfonyl chloride in presence of base such as sodium hydroxide, sodium carbonate, triethylamine, sodium bicarbonate, potassium carbonate, potassium bicarbonate, in various solvents like CH 2 Cl 2 , THF, toluene, DMF, acetonitrile, water; however these reactions were not successful and the required product was not observed under these reaction conditions probably due to the increased steric repulsion of phenyl groups on the incoming tosyl group.In all these attempts, 4-(4-cyanobenzoyl) benzamide 14 was isolated as one of the major product under these conditions, and formation of this product can be attributed to the aerial oxidation of benzylic hydroxyl group at elevated temperature in presence of air/oxygen as well as the less reactivity of 4-((4cyanophenyl)(hydroxy)methyl)benzamide 15 towards the tosylation reaction.Thus, we have decided to peruse halogenations followed by 1H-1,2,4-triazole 4 introduction as the alternate strategy for the synthesis of letrozole 1. Scheme 3. Attempt for the synthesis of tosylate 16.
Attributing to the increased strain may be a probable root cause for the failure of tosylation on compound 15, we focused our attention for converting hydroxyl group in 15 to the chloro derivative 12 (Scheme 4).Thus the alcohol 15 was treated with thionyl chloride in dichloromethane and the required compound 12 was isolated in excellent yields.After the successful synthesis of 12, we focused our attention on the synthesis of the target molecule Letrozole 1 by reacting it with 1H-1,2,4-triazole 4. Several attempts have been carried out for the introduction of 1H-1,2,4-triazole 4 by the nucleophilic substitution on halo compound 12 in presence of a base in polar protic as well as aprotic solvents.All these reactions resulted in poor conversion to the required product.Reaction performed at higher temperatures in presence of polar protic solvents resulted in the formation of 4-(4-cyanobenzoyl) benzamide 14 probably formed via aerial oxidation.However, when the reaction was conducted under neat conditions at elevated temperature (110 °C-120 °C) over a period of 6 h, the required product 11 was isolated in around 75% yield, along with the corresponding regioisomer 17 as shown in Scheme 4.
Scheme 4. Completion of the synthesis of Letrozole 1.

Conclusions
In summary, we have developed a novel and efficient synthetic route for the preparation of Letrozole 1 in excellent yields, which is free from regioisomeric impurities.The developed process utilizes environmentally benign reagents as well as milder reaction conditions.

Experimental Section
General. 1 H and 13 C NMR spectra were recorded in 500 MHz & 125 MHz.All chemical shifts were reported in parts per million (δ) and were internally referenced to residual proton solvents, unless otherwise noted.All spectral data were reported as follows: chemical shift multiplicity [singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m)], coupling constants [Hz].Trifluoroacetic anhydride used in the reaction was distilled from P 2 O 5 and all other chemicals used were purchased from commercial suppliers and used without further purification.All flash column purifications were performed by using silica gel (100-200) mesh.

4-(4-cyanobenzoyl)benzamide (14).
To a solution of compound 13 (25 g, 73.53mmol) in N,Ndimethylacetamide (125mL) was added to potassium ferrocyanide.3H 2 O (31 g, 73.53 mmol) followed by PdCl 2 (0.65 g, 3.6 mmol), and Na 2 CO 3 (15.58g, 147 mmol) at room temperature.The reaction mixture was heated to 100 °C and stirred for 6 h.Later water (2 mL) was added to the reaction mixture and air was purged into the solution at 100°C for 5 h and stirring was continued at the same temperature for 30 h.Then TLC (Thin Layer Chromatography) (10% MeOH/CH 2 Cl 2 ) showed complete conversion to compound 14.The reaction mixture was cooled to room temperature and filtered through celite bed and washed with N, N-DMA (25 mL).To the obtained filtrate added CH 2 Cl 2 (25 mL) and water (250 mL).Stirred the reaction mixture at ambient temperature for 1h.The precipitated product was filtered and dried under vacuo at 60 °C for 8 h afforded 15.7 g (86%) of compound 14 as a pale yellow solid.R f =0. 4