Development of a practical synthesis of etravirine via a microwave-promoted amination

Background Etravirine (ETV) was approved as the second generation drug for use in individuals infected with HIV-1 in 2008 by the U.S. FDA with its unique antiviral activity, high specificity, and low toxicity. However, there are some shortcomings of the existing synthetic routes, such as the long reaction time and poor yield. Results This article describes our efforts to develop an efficient, practical, microwave-promoted synthetic method for one key intermediate of ETV, which is capable of being operated on a scale-up synthesis level. Through this optimized synthetic procedure, the amination reaction time decreased from 12 h to 15 min and the overall yield improved from 30.4 to 38.5%. Conclusion Overall, we developed a practical synthesis of ETV via a microwave-promoted method, and the synthetic procedure could be amenable to scale-up, and production costs could be significantly lowered.

However, there are some shortcomings of the existing synthetic routes, such as the long reaction time and poor yield, which lead to the expensive price of etravirine. Therefore, an efficient synthesis of etravirine holds great potential in both scientifically and socially. 6) are used as starting materials (Schemes 1, 2) [6,7]; (2) Method 2: 4-guanidinobenzonitrile (12) is selected as starting material or intermediate (Schemes 3,4) [8,9].
Treatment of 4 with 4-hydroxy-3,5-dimethylbenzonitrile in N-methylpyrrolidone afforded the key intermediate 5. Then etravirine was obtained by the ammonification reaction of intermediate 5 with ammonia under the condition of high pressure and high temperature.
In another synthetic route (Scheme 2), the starting material 2,4,6-trichloropyrimidine (6) was treated with 4-hydroxy-3,5-dimethylbenzonitrile (7) under the weakly alkaline condition yield the intermediate 8. In Scheme 3, etravirine was obtained with the 4-guanidinobenzonitrile (12) as starting material. Firstly, 12 was cyclized with diethylmalonate in the presence of sodium ethoxide in ethanol to give the intermediate 13, which was subsequently treated with POCl 3 to form the corresponding derivative 14. Then the bromination of 14 afforded the intermediate 4, which passed through four successive reactions (nucleophilic substitution with the sodium salt of 7, and ammonification) to give etravirine. In Scheme 4, the synthesis route very similar to that in Scheme 3. The more commercially available 4-aminobenzonitrile (3) was used as starting material in this route. Besides, the sequence of the last three steps in Scheme 4 (nucleophilic substitution, ammonification and bromination) is distinct from those in Scheme 3.
Taken together, in the above synthesis methods of etravirine, problems like the following still exist: (1) The starting materials are difficult to obtain (exemplified by compound 2); (2) In the route employing 4-guanidinobenzonitrile as starting material or intermediate, the overall yield is low; (3) The longer amination reaction time and lower yield of the overall route when halogenated pyridine was used as starting material. Therefore, there have an urgent need to find more efficient and practicable methods in the pharmaceutical industry to synthesize etravirine and its intermediates. Comparative analysis the existing routes described above, the route in Scheme 2 has advantages of the accessibility of raw materials and the simplicity of synthetic steps. Inspired by the route in Scheme 2 and considering its deficiency, we became interested in designing a more efficient synthesis through optimizing the amination method with the aim to increase the overall yield of the route and shorten the longer amination reaction time.

Results and discussions
Since Gedye and Giguere published their first articles about microwave-assisted syntheses in household microwave ovens in 1986 [10,11], the microwave-assisted synthesis method have attracted an increasing number of chemists' attention for its high efficiency in chemical process. The method have been used in many fields successfully. Considering the longer amination time of the existing process route, we attempt to apply this efficient method in the amination reaction for the purpose of reducing reaction time and improving the yield.
In the preliminary study, we conducted the reaction in an autoclave as the conventional synthesis [5] (Scheme 5). The amination reaction performed very well as the literature reported and the yield ranged from 82.7 to 83.6%. Then we attempted the reaction in the microreactor. When we conducted our first attempt, dioxane, acetonitrile and tetrahydrofuran was used as solvent. The results were frustrated and there no desired product was obtained. We speculated that the poor solubility of the intermediate 9 in these solvent lead to the failure of the reaction. Then some good dissolving solvent of 9 were chosen, such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and N-methylpyrrolidone (NMP). The results were depicted in Table 1, the reaction conducted very well in all the three solvent with moderate to good yield compared to our preliminary attempt. The results demonstrated that the reaction have the best yield in N-methylpyrrolidone, so it was selected as solvent for the further optimization of the microwave reaction. Further investigation of the amination reaction mainly focus on the amination temperature and reaction time ( Table 2). We can conclude that the yield was improved with the increased reaction time and temperature. But there have decreasing tendency of the yield when the temperature above 130 °C and reaction time more than 15 min. After an orthogonal experiment, the optimized conditions of the amination reaction was determined as follows: in the microwave reactor with N-methylpyrrolidone as solvent and reacted in 130 °C for 15 min. The yield of amination reaction can up to 85.6%, which was higher than that of the conventional synthesis method (83.6%). Scheme 3 Synthesis of etravirine with 4-guanidinobenzonitrile (12) as starting material [8] Scheme 4 Synthesis of etravirine with 4-aminobenzonitrile (3) as intermediate [9]

Discussion
The first step of the process route is a typical S N Ar (addition-elimination) process (Scheme 6). Treatment of equimolar amounts of 4-hydroxy-3,5-dimethylbenzonitrile (7) with 2,4,6-trichloropyrimidine (6) in the presence of potassium carbonate may be afford two mono-substituted products 8 and 17 at the position of C 4 -Cl and C 2 -Cl of the staring material 6. But the monosubstituted product 8 were obtained with excellent yields, for the reason that there exist a selectivity between C 4 -Cl and C 2 -Cl of compound 6 [12]. On account of the S N Ar (addition-elimination) process is thermodynamical control, so the product depend on the stabilization of the intermediate Meisenheimer complex. Compared to the Meisenheimer intermediate 16 where the ring nitrogen ortho to the tetrahedral carbon, the intermediate 15 with the para-quinoid structure can be better bear the negative charge and more stabilization [12], which gives reasonable account for the single mono-substituted products 8.

Conclusions
Etravirine is an essential medicine for the treatment of HIV, which is still inaccessible to millions of people worldwide. To overcome the disadvantageous issues in the existing synthetic methods of etravirine, an efficient and practical synthetic method was optimized in this article. The synthesis was achieved using a linear approach starting from 2,4,6-trichloropyrimidine through a sequence of nucleophilic substitution, ammonification and bromination (Scheme 7). The microwavepromoted amination is the most critical step of this route, and it shorten the amination reaction time from 12 h to 15 min. Moreover, the overall yield of the synthetic route is improved from 30.4 to 38.5% over 4 linear steps. To the best of our knowledge, this is the highest yield for etravirine that has been reported. Moreover, all the synthetic process does not require purification by column chromatography, and the formation of impurities could be suppressed very well. Accordingly, the synthetic procedure could be amenable to scale-up, and production costs could be significantly lowered through this microwavepromoted method.

Experimental section
All melting points were determined on a micro melting point apparatus and are uncorrected. 1 H-NMR spectra were obtained on a Bruker Avance 400 NMR spectrometer in the indicated solvents. Chemical shifts are expressed in δ units and TMS as internal reference. Mass spectra was taken on a LC Autos ampler Device: Standard G1313A instrument. TLC was performed on Silica Gel GF254 for TLC (Merck) and spot was visualized by iodine vapours or irradiation with UV light (λ = 254 nm).
The microwave reaction was conducted on a CEM Discover (0-600 W, 2450 MHz) instrument and the conventional high pressure reaction was performed on Parr 4590 instrument. Concentration of the reaction solutions involved the use of rotary evaporator at reduced pressure.

Etravirine (1)
To a cooled solution of 11 (8.4 mmol, 3.0 g) in DCM (30 mL) at 0-5 °C was added bromine solution (9.4 mmol, 1.5 g in 8 mL of DCM). The reaction was stirred at this temperature for 5 h. Then the mixed solution was diluted Scheme 7 Synthetic route and yield of etravirine