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Fast and Convenient Synthesis of Fenclofenac using Ullmann Ether coupling and the Willgerodt-Kindler Reaction under Microwave Conditions
The rapid synthesis of the non-steroidal anti-inflammatory agent Fenclofenac (2-(2,4-dichlorophenoxy)phenyl acetic acid) under microwave irradiation is reported. Modified reaction conditions of traditional Ullmann ether coupling resulted in high yields of the diaryl ether. The WillgerodtKindler transformation and subsequent hydrolysis of thioamide resulted in 52% overall yield of Fenclofenac.

Application Note

O Br O HO O Cl 2b Fenclofenac (1) Cl

Introduction Fenclofenac (1) is a non-steroidal anti-inflammatory drug with analgesic and anti-inflammatory activity.1 Conventionally, the synthesis of Fenclofenac has been undertaken in 3 steps2,3 from 2-chloroacetophenone. However, this conventional approach requires a total reaction time of 5 days and the final yield is relatively low (31%). In recent years, the use of microwave dielectric heating to assist chemical processes has attracted increasing attention. The application of microwave technology to organic synthetic processes has been shown to significantly enhance the speed of reactions.4 This short report describes the efficient synthesis of Fenclofenac (1) using SmithSynthesizer (a single-mode automated microwave instrument). Experimental Procedure Step 1 Preparation of 2-(2,4-Dichlorophenoxy) acetophenone (4) The process vial was charged with CuBrxMe2S (61.7 mg, 0.30 mmol), Cs2CO3 (244 mg, 0.75 mmol) and 2,4-dichlorophenol (3) (122 mg, 0.75 mmol). 2-Bromoacetophenone (2b) (59.7 mg, 0.30 mmol) in MeCN (2.5 mL) was added, followed by 25 L of pyridine. After microwave irradiation at 150C for 30 min., the reaction mixture was diluted with EtOAc (5 mL) and washed with 1N HCl (5 mL) and brine (5 mL) followed by 1N NaOH (5 mL) and brine (5 mL). The organic layer was then dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using petroleum ether/EtOAc (25:1) to give 4 (Rf= 0.37) as a light yellow oil in 88% yield (74 mg).

Step 2 Preparation of 2-(2,4-Dichlorophenoxy) phenylthioacetomorpholide (5) A mixture of the acetophenone (4) (177 mg, 0.63 mmol), sulphur (120 mg, 3.75 mmol) and morpholine (2.5 mL) was heated under microwave irradiation at 150C for 30 min. After cooling, morpholine was removed under vacuum, and the residue was purified by column chromatography using petroleum ether/EtOAc/dichloromethane (9:1:3) to give 5 (Rf=0.33) as an oily residue in 66% yield (159 mg).

O HO +

Cl Step 1 Cl CuBrxMe2S, Cs2CO3 Py, MeCN



Cl 4 O

2 a, X=Cl b, X=Br

3 S N

Cl O Step 3

Step 2 morpholine/S



1) KOH/(CH2OH)2 Cl 2) HCl 5 1


Step 3 2-(2,4-Dichlorophenoxy) phenylacetic Acid (1) A solution of thiomorpholide (5) (76.4 mg, 0.20 mmol) and potassium hydroxide (112 mg, 2.0 mmol) in ethylene glycol (2.5 mL) was heated at 200C for 30 min. Water (2.0 mL) was added and the mixture was washed with ether (3.0 mL). The aqueous layer was acidified with concentrated HCl and extracted into ether (3 x 5 mL). The combined organic extracts were dried (Na2SO4) and evaporated. Purification by column chromatography (petroleum ether/EtOAc/acetic acid, 90:30:5.

Microwave Synthesis Temp/C Step 1 Time Yield Temp/C Conventional3

150 30 min 88% 150 30 min 66% 200 30 min 89% 52%

125 24 min 45% R e f l ux 24 h 75% R e f l ux 72 h 93 % 31%*

Step 2

Time Yield Temp/C

Step 3

Time Yield

Overall Yield

* The yield is estimated for the analogue compound; 2-(2,4-dichloro-5-methylphenoxy)-5-chloro-phenyl acetic acid.

The key step in the synthesis of Fenclofenac (1) is the Ullmann ether coupling of halide (2) with 2,4-dichlorophenol (3). When the procedures outlined in the literature,2 which employ 2chloroacetophenone (2a) as a substrate and the sodium salt of (3) in the presence of catalytic amounts of copper, were tested under microwave irradiation in DMF at 230C for 20 min, low yields of (4) were obtained. Other copper catalysts (CuO and Cu2O) were also tried with no satisfactory results and when the reaction was carried out without any catalyst a very low yield (9%) was observed. The CuBrxSMe2 complex, in the presence of base and a small amount of pyridine,5 was the final choice for catalysis of the reaction between 2-bromoacetophenone (2b) and 2,4-dichlorophenol (3). Cs2CO3 is superior to K2CO3 or NaOH as a base resulting in higher yields. The reaction temperature is also important. When the reaction temperature was increased to 180190C, debromination of 2-bromoacetophenone occurred (2b) resulting in decreased yields. Lower temperatures (100120C) were not sufficient for quantitative conversion. Optimisation of the reaction parameters led to synthesis of diaryl ether (4) in a very good yield.

The second step in the synthesis of Fenclofenac (1) involved carbonyl transformation (the Willgerodt-Kindler reaction) in the presence of sulphur and a secondary amine (morpholine) leading to the terminal thioamide (5). Initial experiments under microwave conditions resulted in low yields of product and some unidentified by-products, probably caused by the large excess of morpholine. When DMF was used as a solvent instead of morpholine, there was no significant increase in the yields. It became apparent that the concentrations of the reaction components are crucial for the Willgerodt reaction. When the concentration of the starting material (4) was increased to 0.20 mmol/mL a 74% HPLC purity of thioamide (5) was achieved.
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The final step in the synthesis of Fenclofenac (1) was hydrolysis of thiomorpholide (5), a reaction that conventionally requires prolonged reaction times of up to 72 hours. Although microwave irradiation with 20 eq of KOH in methanol at 160C allowed a significant reduction in the reaction time (from 72 h to 1.5 h), conditions for quantitative hydrolysis were inconvenient from a practical point of view (long reaction time andvery high pressure, ~17 bars). Changing the solvent to ethylene glycol, however, allowed satisfactory conversion of thioamide (5) to Fenclofenac (1) with an overall yield of 52% from 2-bromoacetophenone (2b) (31% with conventional heating). Conclusion This report summarizes a convenient approach to the synthesis of Fenclofenac. The reaction time has been decreased from 5 days to 1.5 h with an improvement in total yield from 31% to 52%. The user-friendly software of Microwave Synthesis in combination with highly automated

dispensing and heating devices allowed the speedy optimization of the reactions. Parameters such as solvent, catalyst, concentration and reagent stochiometry turned out to have a great influence on the outcome of the synthesis of Fenclofenac.

References 1. Kleemann, A. et al., Pharmazeutische Wirkstoffe Georg Thieme Verlag: NewYork, 1982; pp. 388-389. 2. Ger. Pat. 2,117,826 (Reckitt&Colman) 1971. 3. Atkinson, D.C. et al., J.Med. Chem. 1983, 26,1353-1360. 4. Larhed, M., Hallberg, A.Drug Discovery Today 2001, 6, 406-416.; Lidstrm, P., Tierney, J., Wathey, B. and Westman, J. Tetrahedron 2001, 57,9225-9283. 5. Nicolaou, K.C. et al., J. Am.Chem. Soc. 1997, 119, 3421-3422.

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