( 4-Isobutyl-phenyl )-acetic acid ( Ibufenac ) Microwave-Assisted and Conventional Synthesis

The multigrams synthesis of Ibufenac is reported and the results of conventional and microwave heating are compared.


Introduction
Ibufenac 2 was used as a non-steroidal anti-inflammatory drug (NSAID) 1 until it was taken off the market because of hepatotoxicity. 2As the title compound is commercially available in mg quantities only we needed to prepare it in the context of joint collaboration in the chemogenomics project DrugMatrix. 3

Results and Discussion
In recent years, the use of microwave dielectric heating to assist chemical processes has attracted increasing attention in organic and medicinal chemistry community and the application of the Microwave-assisted Organic Synthesis (MAOS) protocols has been shown to significantly enhance the speed of reactions. 4In particular, the use of dedicated microwave reactors that enable the rapid and safe heating of reaction mixtures in sealed vessels under controlled conditions with on-line temperature and pressure monitoring has greatly increased the general acceptance of the microwave heating method.

Scheme 1
It appeared to us that the use of microwave heating using sealed vessel (autoclave) would provide a rapid method to synthesize phenyl acetic acids. 5,6It should be noted that the first reports on microwave-assisted Willgerodt-Kindler processes have appeared in the literature 7 these studies employed domestic microwave ovens that did not allow accurate temperature measurements and therefore, may prove difficult to reproduce. 4,5 report here a microwave enhanced Willgerodt-Kindler synthesis of the thiomorpholide and hydrolysis of this compound to Ibufenac with taking advantage of the sealed vessel capabilities of a dedicated single-mode microwave reactor, CEM Explorer™ 6 (a single mode automated microwave instrument (Fig. 1), the comparison with conventional heating with significant yield improvement.
Fig. 1 CEM Explorer™ and Single-mode cavity design.
The reaction under solvent free conditions at different temperature and reaction time yielded 78-85% of the thiomorpholide 1 but using 1-methyl-2-pyrrolidone (NMP) as solvent the yield was increased to 94%.(Table 1) The hydrolysis with aq.NaOH solution at 150 °C for 20 min.
applying microwave was not sufficient to complete reaction.However, the hydrolysis by adding alcoholic KOH (3N) to the reaction mixture and employing microwave heating for 20 min at 150°C resulted in 98% conversion.(HPLC) The three-component condensation of 4-isobutylacetophenone, morpholine and elemental sulfur using NMP as solvent also was carried out employing microwave flash heating at 160 °C for 20 min.Then alcoholic solution of KOH (3N) was added to the reaction mixture and irradiation continued for 20 min.at 150 °C.
Although microwave irradiation allowed a significant reduction in the reaction time, conditions for preparation of 30 g of Ibufenac were inconvenient from a practical point of view.This would be convenient just using scale up microwave instrument (e.g.Synthos 3000 TM ).

General microwave assisted procedure
Step 1 Step 2

Preparation of Ibufenac (2)
To the reaction mixture of the step 1 according to

Preparation of Ibufenac (2)
To the reaction mixture of the step 1 alcoholic KOH (250 mL, 3N) was added and stirred at 110°C for 12 h.After cooling, 200 mL water was added to the reaction mixture and washed with Et 2 O (3×mL) then acidified by HCl 2N (pH=2) and extracted to dichloromethane.The organic phase was dried over Na 2 SO 4 , decolorized with activated carbon, filtered and evaporated under vacuum to yield the product as a yellow solid.The product was recrystallized from EtOH: water (1:1, 250 mL) to yield 2 (27.3 g, 95%) with >99% HPLC purity.

CONCLUSION
This report summarizes a convenient approach to the synthesis of Ibufenac.The reaction time has been decreased from 22 hours conventional to 30 min.microwave dielectric heating with total yield 95%.

Table 2 -
6,9However for quick preparation of smaller scale and diverse libraries MAOS protocol would be an ideal opportunity.(SeeTable1,2)Optimization of the hydrolysis, Ibufenac preparation.
EXPERIMENTALMelting points were measured on a Kofler micro hot stage.NMR-spectra were recorded on a Bruker AC-200 in CDCl3.Thin layer chromatography (TLC) was performed on pre-coated plates (Merck TLC aluminum sheets silica 60 F254) with detection by UV light or with phosphomolybdic acid in aqueous EtOH by heating.For reaction monitoring and quality (purity) control of the product a Waters 996 HPLC system, that included Waters 600-MS pumps, an autosampler (Waters 712 WISP), and Waters 996 photodiode array UV detector was used.The separations were carried out using a Chromolith Performance reversed phase analytical column (E.Merck, 100 × 4.6 mm) at 25 °C and a mobile phase from (A) 0.1% TFA in 97:3 water/MeCN and (B) 0.1% TFA in MeCN (all solvents were HPLC grade, Fisher and Merck; TFA was Teflon septa and aluminum crimper.After microwave irradiation according to table 1, the reaction mixture was monitored by HPLC and directly used for step 2.An analytical sample for structure verification was prepared.Mp 69 °C (Lit. 1062°C), 1 H-NMR in CDCl 3 δ ppm, 7.17 (dd,