Thin-layer chromatography (TLC) was performed on Silica Gel GF254 for TLC (Merck), and spots were visualized by irradiation with UV light (λ = 254 nm). 1H NMR and 13C NMR spectra were recorded on a Bruker AV-400 NMR spectrometer or a Bruker Avance-600 NMR spectrometer using solvents as indicated. Chemical shifts were reported in δ values (ppm) with tetramethylsilane as the internal reference, and J values were reported in hertz (Hz). Melting points (m.p.) were determined on a micro melting point apparatus (TianJin Analytical Instrument Factory, Nankai, Tianjin, China). Mass spectra were recorded on an LC Autosampler device: Standard G1313A instrument. 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 device. Rotary evaporators were served in the concentration of the reaction solutions under reduced pressure.
5.1. (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (2)
To a round-bottomed flask consisting of 10 mL of phosphorus oxychloride was added compound 6 slowly at 0 ℃ and then refluxed for 8 h at 40 ℃. After completion of the reaction was monitored by TLC, and the reaction mixture was slowly poured into the ice-water mixture and stirred for 1 hour and then filtered to obtain the crude (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile (7) as white crystal solid.
The obtained crude product 7 was dissolved in anhydrous ethanol, and then added ethanolic hydrochloric acid solution, and stirred for 30 min, then filtered to obtain (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (2). Yield: 95%. mp: 78–80℃. 1H NMR (400 MHz, CDCl3): δ 7.22 (d, J = 16.5 Hz, 1H,CH=), 7.05 (s, 2H, Ph-H), 5.59 (d, J = 16.5 Hz, 1H, =CH), 3.95 (s, 2H, NH), 2.18 (s, 6H, CH3). 13C NMR (100 MHz, CDCl3): δ 150.94, 146.21, 129.86, 128.02, 123.28, 121.50, 119.60, 90.28, 77.38, 77.06, 76.74, 17.50. ESI-MS: m/z 173.54 [M + H]+, C11H12N2 (172.10).
5.2. Preparation of ethanolic hydrochloric acid solution
The solvent of anhydrous ethanol was stirred under ice bath, and then 41 mL of acetyl chloride reagent added slowly dropwise and stirred for 30 min to obtain an ethanolic hydrochloric acid solution.
5.3. 4-((4-hydroxypyrimidin-2-yl)amino)benzonitrile (13)
Starting materials 2-methylthio-4-pyrimidinone 11 (70 mmol, 10 g) and p-aminobenzonitrile 12 (77 mmol, 9.14 g) were taken together, stirred under the inert condition at 160 °C for 2 h and then increased the temperature to 180 °C for 4 h. Then the reaction was allowed to room temperature and added an appropriate amount of N, N-dimethylformamide. The resulted mixture was kept in the ultrasonic vibrator for 30 min. Then the mixture was filtered and washed with acetonitrile and dichloromethane, dried in vacuo to give 4-((4-hydroxypyrimidin-2-yl)amino)benzonitrile (13) as a white solid (10.3 g, yield 70%).
5.4. 4-((4-chloropyrimidin-2-yl)amino)benzonitrile (3)
Compound 13 was dissolved in 20 mL of phosphorus oxychloride at 0 ℃ and then refluxed for one hour. After completion, the mixture was cooled to room temperature, slowly poured into 100 g of crushed ice and stirred for half an hour. After filtration, the obtained filter cake was dissolved in 50 mL of water, and the pH was adjusted to 7–8 with potassium carbonate and filtered. The filtrate was washed with acetonitrile and dried to obtain 4-((4-chloropyrimidin-2-yl)amino)benzonitrile (3) as a white solid (9.9 g). Yield: 89%. mp: 209–210 ℃. 1H NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H, C6-pyrimidine-H), 7.87 (dd, 4H, Ph-H), 7.13 (d, J = 5.2 Hz, 1H, C6-pyrimidine-H); ESI-MS: m/z 231. 2 [M + H]+, C11H7ClN4 (230.04).
5.5. Rilpivirine (1)
A mixture of compound 2 (1 g, 4.8 mmol) and 3 (1.2 g, 5.2 mmol) along with 10 mL acetonitrile was transferred into 20 mL microwave vial and set the reaction temperature at 140 °C, 2 h. After completion, the reaction mixture was cooled to room temperature and then 10% potassium carbonate solution was added dropwise to the vial to adjust the pH to 8–9. The obtained filtrate was washed with acetonitrile to obtain the target molecule rilpivirine as a white solid (1.28 g). Yield 71%. mp: 138–140 ℃. 1H NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H, NH), 8.95 (s, 1H, NH), 7.98 (t, J = 27.2 Hz, 2H, Ph-H), 7.69 (m, 3H, =CH, Ph-H), 7.49 (s, 2H, Ph-H), 6.46 (d, J = 16.7 Hz, 1H, =CH), 2.18 (s, 6H, CH3). ESI-MS: m/z 367.24 [M + H]+, C22H18N6 (366.16).