*3.1.6 Synthesis of etravirine; (TMC 125); 2,4-[[6-amino-5-bromo-2-[(4-cyanophenyl) amino]-4-pyrimidinyl] oxy]-3,5-dimethylbenzonitrile (63)]*

Etravirine is a novel diarylpyrimidine, second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of human immunodeficiency virus type 1 infection, which has been approved by the U.S. Federal Drug Administration for the treatment of AIDS in the year 2008 [80, 96–98].

*Synthetic Approaches for Pharmacologically Active Decorated Six-Membered Diazines DOI: http://dx.doi.org/10.5772/intechopen.109103*

#### **Figure 31.**

*Synthesis of 2-Amino-4,5,6-Trisubstituted pyrimidine derivatives. Reagents and conditions: a) N-me-piperazine, Et3N, EtOH, Δ; b) compounds (160a-160 m): Intermediate (157), R7/R8-Ph-B(OH)2, Pd(PPh3)4, Na2CO3, 1,2-dimethoxyethane, Δ; c) compounds (161a-160o): Intermediate (157), the corresponding amine, 2 ethoxyethanol, Hunig's base, 110–140°C; d) Ullmann conditions: Intermediate (157), corresponding heterocycle, CuI, K2CO3, DMF, 130°C; and (iii) NaI, 47% aqueous HI, 80°C, 98% [94].*

It is a potent inhibitor of HIV reverse transcriptase [98], and active against NNRTI-Resistant Strains of HIV, by its ability to adapt its binding orientation and overcome common NNRTI resistance associated mutations (RAMs) such as K103N and achieving viral suppression and improving the immune function in treatmentexperienced HIV-infected patients [99].

The synthesis of Etravirine (63) is fraught with many difficulties, the foremost being the poor yield and long reaction time required at the aminolysis stage [100].

The most efficient approach to overcome the mentioned disadvantages is four linear steps where the microwave promoted amination is the most critical one of these routes, as it shortens the amination reaction time from 12 h to 15 min, and improve the overall yield of the synthetic route from 30.4 to 38.5% (**Figure 32**) [100].

2,4,6-trichloropyrimidine (109) was first reacted with 4-hydroxy-3,5-dimethylbenzonitrile (162) in the presence of diisopropylethylamine in refluxing dioxane and heated at 70°C for 2 hours, to give the biaryl ether derivative: 4-[(2,6-dichloro)-4 pyrimidinyloxy]-3,5-dimethylbenzonitrile (163) [96].

The second substitution reaction with aniline derivative 4- aminobenzonitrile (164) using potassium tert-butoxide as a base and N-methylpyrrolidone as a solvent over a period of 30 min and stirred for another 2 h at 0–5°C, to give compound 4-[[6- Chloro-2-[(4-cyanophenyl) amino]-4-pyrimidinyl] oxy]3,5-dimethylbenzonitrile (165) with a yield of 60.6%. The aminolysis of (165) went smoothly using 25% aq ammonia (15 mL), and N-methylpyrrolidone (20 mL) at temp 130°C, for 15 min in a microwave reactor, then the reaction mixture was brought to 5–10°C, 100 mL water

#### **Figure 32.**

*Synthesis of Etravirine (63). Reagents and conditions: a) DIEA in refluxing dioxane, 70°C, 2 hours, 92.5%; b) potassium tert-butoxide, N-methylpyrrolidone, 30 min and stirred for another 2 h at 0–5°C, 60.6%; c) 25% aq NH3, N-methylpyrrolidone, 130°C, 15 min in a microwave reactor, 5–10°C, 100 mL water, stir 30 min. Filter, wash with 100 mL H2O, dry at 45–50°C, 85.6%; d) Br2, DCM, 0–5°C, stirring 5 h, 80.2%.*

was added to this solution followed stirring another 30 min. The generated solid was filtered, washed with 100 mL of water and dried at 45–50°C to give the amine: 4-[[6 amino-2-[(4-cyanophenyl) amino]-4-pyrimidinyl] oxy]3,5-dimethylbenzonitrile (166) in good yield (85.6%).

Finally, bromination of (166) was conducted in the presence of liquid bromine in DCM at 0–5°C, the reaction was stirred at this temperature for 5 h to give etravirine (63) in 80.2% yield [96].
