PROCESS FOR THE PREPARATION OF RILPIVIRINE

Abstract

The present invention relates to a new process of preparation of Rilpivirine, or a pharmaceutically acceptable salt thereof. Another aspect of the invention concerns compounds of formulae II and III: and their salts thereof, and their use for the preparation of Rilpivirine or a suitable salt thereof.

##STR00001##

Claims

1. A process for the preparation of Rilpivirine, or a pharmaceutically acceptable salt or solvate thereof, comprising the following steps: a) preparing a compound of formula II: ##STR00035##  wherein A is an amine protecting group selected from alkyloxycarbonyl, arylalkyloxycarbonyl, alkylcarbonyl, arylsulfonyl, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl and arylalkyl, b) reacting said compound of formula II with a 2,4-dihalogenopyrimidine in the presence of a base to obtain compound of formula III: ##STR00036##  wherein A is an amine protecting group selected from alkyloxycarbonyl, arylalkyloxycarbonyl, alkylcarbonyl, arylsulfonyl, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl and arylalkyl and X is a halogen, c) reacting said compound of formula III with 4-aminobenzonitrile in the presence of an acid, and d) cleaving the group A, wherein steps a), b, and c) are carried out successively in this order and step d) is carried out concomitantly with step c) or after step c).

2. The process according to claim 1, wherein the amine protecting group is selected from alkyloxycarbonyl, arylsulfonyl and alkylsulfonyl.

3. The process according to claim 1, wherein the base used in step b) is selected from alkali metal salts of alcohols and amides.

4. The process according to claim 1, wherein the solvent used in step b) is selected from polar aprotic solvents and aromatic non-polar solvents.

5. The process according to claim 1, wherein step b) is run at a temperature ranging from 10° C. to 60° C.

6. The process according to claim 1, wherein the acid used in step c) is selected from acetic acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, any supported acidic catalyst and mixtures thereof.

7. The process according to claim 1, wherein the step c) is performed in a solvent selected from polar solvents and aromatic non-polar solvents, optionally as a mixture with water.

8. The process according to claim 1, wherein step c) is performed at a temperature ranging from 50° C. to 200° C.

9. The process according to claim 1 resulting in polymorphic form A of Rilpivirine hydrochloride, wherein the compound of formula III is reacted in step c) with 4-aminobenzonitrile in the presence of hydrochloric acid and wherein step d) is carried out concomitantly with step c) using a mixture of glacial acetic acid and water as solvent.

10. A compound of formula II: ##STR00037## or a pharmaceutically acceptable salt thereof, wherein A is an amine protecting group selected from alkyloxycarbonyl, alkylcarbonyl, arylsulfonyl, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl and arylalkyl.

11. The compound according to claim 10, wherein the amine protecting group is selected from alkyloxycarbonyl, arylsulfonyl and alkylsulfonyl.

12. A compound of formula III: ##STR00038## or a pharmaceutically acceptable salt thereof, wherein A is an amine protecting group selected from alkyloxycarbonyl, arylalkyloxycarbonyl, alkylcarbonyl, arylsulfonyl, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl and arylalkyl and X is a halogen.

13. The compound according to claim 12, wherein the amine protecting group is selected from alkyloxycarbonyl, arylsulfonyl and alkylsulfonyl.

14. Use of compound according to claim 10 as a synthetic intermediate for the preparation of Rilpivirine or a pharmaceutically acceptable salt or solvate thereof.

15. Use of compound according to claim 12 as a synthetic intermediate for the preparation of Rilpivirine or a pharmaceutically acceptable salt or solvate thereof.

Description

FIGURES

[0104] FIG. 1: X-ray powder diffraction powder of hydrochloride salt of Rilpivirine (polymorphic form A) obtained by the process according to the invention in comparison with the data of U.S. Pat. No. 7,956,063 B2.

EXAMPLES

[0105] All temperatures are expressed in ° C. and all reactions were carried out at room temperature (RT) unless otherwise stated.

[0106] The reaction monitoring was performed by reverse phase HPLC

[0107] NMR spectra were recorded on Bruker Avance 300 (operating at 300 MHz for .sup.1H and 75 MHz for .sup.13C) or Oxford Instrument Pulsar (operating at 60 MHz for .sup.1H). Chemical shifts are expressed in ppm relative to tetramethylsilane (TMS) or to residual proton signal in deuterated solvents. Chemical shifts are reported as position (δ in ppm), multiplicity (s=singulet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad), coupling constant (J in Hz) and relative integral.

[0108] The purity of final compounds was determined by high pressure liquid chromatography (HPLC) using Agilent apparatus fitted with a Zorbax SB phenyl column (150×6.6 mm, 3.5 μm) using a mixture of H.sub.2O (+0.1% H.sub.3PO.sub.4) and CH.sub.3CN as eluent.

[0109] The melting point analyses were performed on Mettler Toledo DSC 3

[0110] Solvents, reagents and starting materials were purchased from well-known chemical suppliers (such as for example Sigma Aldrich, Acros Organics, Fluorochem, Eurisotop, VWR International, ABCR, TCI) and the following abbreviations are used:

[0111] HPLC: high performance liquid chromatography

[0112] DSC: differential scanning calorimetry

[0113] m.p. melting point

[0114] LCAP: Liquid Chromatography Area Percentage

Example 1

[0115] ##STR00015##

[0116] Salt break of (2E)-3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile hydrochloride.

##STR00016##

[0117] In a round bottomed flask, equipped with a mechanical stirrer, a water condenser and a temperature controller, (2E)-3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile hydrochloride (100 g), 2-methyl-tetrahydrofuran (500 mL) and deionized water (200 mL) are introduced. The mixture is heated at 40° C. and a 30% by weight aqueous solution of sodium hydroxide (64 g) is added. After 1 h, the layers are separated, the organic layer is washed with deionized water (50 mL). The solvent is evaporated, the residue (82.7 g, quantitative yield) is diluted with 2-methyl-tetrahydrofuran (150 mL) and is used directly in the next step.

[0118] Synthesis of tert-butyl {4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}carbamate 1.

##STR00017##

[0119] In a round bottomed flask, equipped with a mechanical stirrer, a water condenser, a temperature controller, under inert gas, (2E)-3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile in 2-methyl-tetrahydrofuran from previous step is heated to reflux. A solution of di-tert-butyl dicarbonate in 2-methyl-tetrahydrofuran (299 g of a 70% by weight solution) is added and the resulting mixture is refluxed overnight. After this period of time, 2-methyl-tetrahydrofuran is evaporated, the residue is taken up in dimethylsulfoxide (300 mL). The solvent is evaporated and the residue is taken up in dimethylsulfoxide (300 mL). The solvent is evaporated and the residue is taken up in dimethylsulfoxide (200 mL). The resulting solution containing tert-butyl {4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}carbamate (118 g, 90% yield) is used directly in the next step.

[0120] m.p. (DSC) 153° C.

[0121] .sup.1H NMR (60 MHz, CDCl.sub.3): δ (ppm) 7.28 (d, J=10.9 Hz, 1H), 7.08 (s, 2H), 5.85 (s, 1H), 5.71 (d, J=16.5 Hz, 1H), 2.21 (s, 6H), 1.42 (s, 9H). All signals appear broad.

[0122] Synthesis of tert-butyl (2-chloropyrimidin-4-yl){4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}carbamate 2.

##STR00018##

[0123] In a round bottomed flask, equipped with a mechanical stirrer, a water condenser, a temperature controller, under inert gas, sodium tert-amylate (58 g) and dimethylsulfoxide (250 mL) are added and stirred until a clear solution is obtained. A solution containing tert-butyl {4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}carbamate (118 g) in dimethylsulfoxide (200 mL) is added. The resulting mixture is stirred at room temperature for 1 h. After this period of time, it is transferred to a solution of 2,4-dichloropyrimidine (86 g) in dimethylsulfoxide (200 mL). The resulting mixture is kept under stirring for 1 h before quenching on a mixture of water and n-butanol at 60° C. The resulting solid was collected by filtration and dried to obtain tert-butyl (2-chloropyrimidin-4-yl){4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}carbamate (147 g, 80% yield). Purity of the product was found to be 95.3% as assayed by HPLC.

[0124] Crude tert-butyl (2-chloropyrimidin-4-yl){4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}carbamate (52 g) was dissolved in n-butanol, the mixture is heated to reflux and maintained until a clear solution is obtained. After cooling, the solid is filtered and dried to afford tert-butyl (2-chloropyrimidin-4-yl){4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}carbamate (45 g, 87% yield). Purity of the product was found to be 99.0% as assayed by HPLC.

[0125] m.p. (DSC) 143° C.

[0126] .sup.1H NMR (300 MHz, DMSO): δ (ppm) 8.64 (d, J=5.9 Hz, 1H), 8.09 (d, J=5.9 Hz, 1H), 7.61 (d, J=16.7 Hz, 1H), 7.48 (s, 2H), 6.47 (d, J=16.7 Hz, 1H), 2.02 (s, 6H), 1.35 (s, 9H).

[0127] .sup.13C NMR (75 MHz, DMSO): δ (ppm) 160.8, 160.5, 159.0, 151.1, 149.9, 139.3, 136.1 (2C), 133.3, 127.6 (2C), 118.8, 110.5, 97.3, 83.3, 27.3 (3C), 17.3 (2C).

[0128] Synthesis of 4-[(4-{4-[(E)-2-cyanoethenyl]-2,6-dimethylanilino}pyrimidin-2-yl)amino]benzonitrile hydrochloride (Rilpivirine hydrochloride).

##STR00019##

[0129] In a round bottomed flask, equipped with a mechanical stirrer, a water condenser, a temperature controller, under inert gas, 4-aminobenzonitrile (4.6 g), glacial acetic acid (7.5 mL), deionized water (7.5 mL) are heated to reflux. A 34% by weight aqueous solution of hydrochloric acid (1.4 g) is added. Tert-butyl (2-chloropyrimidin-4-yl){4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}carbamate (5.0 g) is added as a solution in glacial acetic acid (15 mL). The mixture is refluxed for 1 h. After cooling, the solid is filtered and dried to give 4-[(4-{4-[(E)-2-cyanoethenyl]-2,6-dimethylanilino}pyrimidin-2-yl)amino]benzonitrile hydrochloride (3.7 g, 71% yield). Purity of the product was found to be 93.9% by LCAP.

[0130] 4-[(4-{4-[(E)-2-cyanoethenyl]-2,6-dimethylanilino}pyrimidin-2-yl)amino]benzonitrile hydrochloride (3.5 g) was suspended in glacial acetic acid (21 mL) and deionized water (21 mL), the mixture is refluxed until a clear solution is obtained. After cooling, the solid is filtered and dried to afford purified 4-[(4-{4-[(E)-2-cyanoethenyl]-2,6-dimethylanilino}pyrimidin-2-yl)amino]benzonitrile hydrochloride (2.9 g, 83% yield). Purity of the product was found to be 99.7% by LCAP.

[0131] The identity of the product was confirmed by mass spectrometry, comparison with an authentic sample by HPLC and comparisons of experimental .sup.1H NMR spectrum and XRPD pattern with literature data (U.S. Pat. No. 7,956,063 B2). The product was unambiguously identified as the A form (anhydrous hydrochloride) of rilpivirine as shown on FIG. 1.

[0132] m.p.>290° C. dec. (DSC).

[0133] .sup.1H NMR (300 MHz, DMSO): δ (ppm) 11.27 (s, 1H), 10.92 (s, 1H), 8.12 (d, J=6.9 Hz, 1H), 8.02-7.80 (m, 1H), 7.69 (d, J=16.7 Hz, 1H), 7.54 (s, 2H), 7.42 (dd, J=22.7, 8.1 Hz, 3H), 6.67 (d, J=6.9 Hz, 1H), 6.53 (d, J=16.7 Hz, 1H), 2.18 (s, 6H).

Example 2

[0134] ##STR00020##

[0135] Synthesis of methyl {4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}-carbamate 1a.

##STR00021##

[0136] In a round bottom flask under nitrogen were mixed (E)-3-(4amino-3,5-dimethylphenyl)acrylonitrile (1 g, 6 mmol, 1 equiv) and N,N-diisopropylethylamine (1.7 mL, 9.6 mmol, 1.6 equiv) in dry dichloromethane (20 mL). The mixture was cooled to 0° C. before the dropwise addition of methyl chloroformate (0.7 mL, 9.0 mmol, 1.5 equiv). The reaction was allowed to warm up to room temperature and stirred for 72 h. The resulting mixture was then washed with a 1 M aqueous solution of hydrochloric acid and water before drying the organic layer over anhydrous sodium sulfate and concentrating down. Recrystallization of the crude solid in hot ethyl acetate gave the desired compound as a light brown solid (860 mg, 62%).

[0137] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm)=7.31 (dt, J=16.6, 0.6 Hz, 1H), 7.18-7.12 (m, 2H), 5.82 (d, J=16.6 Hz, 1H), 3.76 (br. s, 3H), 2.30-2.26 (m, 6H).

[0138] .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm)=150.2, 136.6, 132.3, 127.4, 118.3, 96.4, 52.8, 18.6.

[0139] MS (ESI): m/z=229.0 (M−H).sup.−

[0140] Synthesis of methyl (2-chloropyrimidin-4-yl){4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}carbamate 2a.

##STR00022##

[0141] In a reaction vial under nitrogen, was dissolved sodium tert-amylate (462 mg, 4.2 mmol, 1.2 equiv) in dry dimethylsulfoxide (2 mL). The resulting mixture was stirred for 1 h until a clear solution was obtained before the dropwise addition of a solution of methyl (E)-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)carbamate 1a (800 mg, 3.5 mmol, 1.0 equiv) in dry dimethylsulfoxide (2 mL). The stirring was continued for 1 h before its dropwise transfer to a solution of 2,4-dichloropyrimidine (678 mg, 4.6 mmol, 1.3 equiv) in dry dimethylsulfoxide (1.5 mL). After 1 h, water is added, the desired product was collected by filtration and dried under vacuum to afford a pale brown solid (1.0 g, 84%).

[0142] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm)=8.51 (d, J=5.9 Hz, 1H), 8.15 (d, J=5.9 Hz, 1H), 7.36 (dt, J=16.6, 0.5 Hz, 1H), 7.22 (h, J=0.6 Hz, 2H), 5.89 (d, J=16.6 Hz, 1H), 3.78 (s, 3H), 2.10-2.04 (m, 6H).

[0143] .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm)=161.1, 160.5, 160.0, 153.9, 150.0, 139.2, 137.1, 133.6, 127.6, 118.2, 110.0, 97.1, 54.5, 18.1.

[0144] MS (ESI): m/z=343.1 (M+H).sup.+

[0145] Synthesis of methyl (E)-(2-((4-cyanophenyl)amino)pyrimidin-4-yl)(4-(2-cyanoethenyl)-2,6-dimethylphenyl)carbamate 3a

##STR00023##

[0146] In a reaction vial were heated to reflux a mixture of 4-aminobenzonitrile (886 mg, 7.5 mmol, 3.0 equiv) in a 1:1 mixture of acetic acid and deionized water (3 mL). 37% hydrochloric acid in water was added (240 μL, 2.9 mmol, 1.2 equiv) before the introduction of a solution of methyl (E)-(2-chloropyrimidin-4-yl)(4-(2-cyanovinyl)-2,6-dimethylphenyl)carbamate 2a (857 mg, 2.5 mmol, 1.0 equiv) in acetic acid (9 mL). The reflux was kept for one hour before cooling down the resulting mixture. Water was added and the desired product precipitated. The crude solid was then dissolved in ethyl acetate and washed with a saturated solution of sodium hydrogen carbonate, followed by brine. Organics were dried over anhydrous sodium sulfate and concentrated down to give the desired product (780 mg, 73%).

[0147] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm)=8.40 (d, J=5.8 Hz, 1H), 7.79 (d, J=5.8 Hz, 1H), 7.47 (d, J=16.6 Hz, 1H), 7.41 (br. s, 1H), 7.31 (s, 2H), 7.23-7.18 (m, 2H), 7.07-7.01 (m, 2H), 5.98 (d, J=16.6 Hz, 1H), 3.78 (s, 3H), 2.11 (s, 6H).

[0148] .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm)=160.1, 159.4, 158.5, 153.9, 149.6, 143.4, 140.5, 137.6, 133.5, 132.9, 127.5, 119.3, 117.9, 117.7, 104.4, 103.9, 97.6, 54.3, 18.1.

[0149] MS (ESI): m/z=425.1 (M+H).sup.+

[0150] Synthesis of 4-[(4-{4-[(E)-2-cyanoethenyl]-2,6-dimethylanilino}pyrimidin-2-yl)amino]benzonitrile hydrochloride (Rilpivirine hydrochloride).

##STR00024##

[0151] In a microwave tube were mixed methyl (E)-(2-((4-cyanophenyl)amino)pyrimidin-4-yl)(4-(2-cyanoethenyl)-2,6-dimethylphenyl)carbamate 3a (127 mg, 0.3 mmol, 1 equiv) and lithium chloride (127 mg, 3 mmol, 10 equiv) in acetic acid (1.5 mL). The reaction was heated by microwave irradiation during 3 cycles of 20 min at 150° C. Water was then added and the mixture was extracted with ethyl acetate. Organics were washed with a saturated aqueous solution of sodium hydrogen carbonate before drying over anhydrous sodium sulfate and concentration. The crude mixture was purified by flash chromatography (SiO.sub.2, petroleum ether/ethyl acetate 6:1 to 1:1) to give 64 mg of Rilpivirine free base (40%) 44 mg of the free base (0.12 mmol) was dissolved in boiling isopropanol (5 mL) and 37% aqueous hydrochloric acid was added (10 μL, 0.12 mmol, 1 equiv). The mixture was cooled down, and the desired Rilpivirine hydrochloride was collected by filtration (38.5 mg, 80%).

[0152] .sup.1H, .sup.13C NMR and MS matched the analytical reference.

Example 3

[0153] ##STR00025##

[0154] Synthesis of (E)-N-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)-4-methylbenzene-sulfonamide 1b

##STR00026##

[0155] In a round bottom flask under nitrogen were mixed (E)-3-(4amino-3,5-dimethylphenyl)acrylonitrile (1.0 g, 6.0 mmol, 1.0 equiv) and pyridine (956 μL, 12 mmol, 2.0 equiv) in dry dichloromethane (20 mL). The mixture was cooled to 0° C. before the portionwise addition of tosyl chloride (2.3 g, 12 mmol, 2.0 equiv). The reaction was allowed to warm up to room temperature and stirred for 72 h. The mixture was then washed with a 1 M aqueous solution of hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and finally water before drying the organic layer over anhydrous sodium sulfate and concentration. The crude solid was recrystallized from a mixture of petroleum ether and ethyl acetate to give the desired compound as a brown solid (1.25 g, 63%).

[0156] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm)=7.59-7.55 (m, 2H), 7.27-7.21 (m, 3H), 7.06 (br. s, 2H), 6.47 (br. s, 1H), 2.40 (s, 3H), 2.03 (s, 6H).

[0157] .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm)=149.9, 144.1, 138.7, 137.6, 135.5, 132.6, 129.9, 127.8, 127.2, 118.2, 96.8, 21.7, 18.9.

[0158] MS (ESI) m/z=325.0 (M−H).sup.−

[0159] Synthesis of (E)-N-(2-chloropyrimidin-4-yl)-N-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)-4-methylbenzenesulfonamide 2b

##STR00027##

[0160] In a reaction vial under nitrogen, was dissolved sodium tert-amylate (396 mg, 3.6 mmol, 1.2 equiv) in dry dimethylsulfoxide (1.6 mL). The resulting mixture was stirred for 1 h until a clear solution was obtained before the dropwise addition of a solution of (E)-N-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)-4-methylbenzenesulfonamide 2a (986 mg, 3.0 mmol, 1.0 equiv) in dry dimethylsulfoxide (1.6 mL). The stirring was continued for 1 h before its dropwise transfer to a solution of 2,4-dichloropyrimidine (582 mg, 3.9 mmol, 1.3 equiv) in dry dimethylsulfoxide (1.5 mL). After 96 h, the mixture was filtered and the resulting solid washed with dimethylsulfoxide to give title compound as a beige solid (840 mg, 80%).

[0161] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm)=8.22-8.16 (m, 3H), 7.40-7.34 (m, 3H), 7.31 (br. s, 2H), 5.97-5.91 (m, 2H), 2.47 (s, 3H), 2.17 (s, 6H).

[0162] .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm)=160.3, 160.2, 159.7, 149.3, 145.7, 140.0, 136.8, 136.1, 134.9, 130.9, 129.3, 128.4, 117.9, 105.4, 98.5, 21.9, 19.0.

[0163] MS (ESI) m/z=439.1 (M+H)

[0164] Synthesis of (E)-N-(2-((4-cyanophenyl)amino)pyrimidin-4-yl)-N-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)-4-methylbenzenesulfonamide 3b

##STR00028##

[0165] In a reaction vial were heated to reflux a mixture of 4-aminobenzonitrile (850 mg, 7.2 mmol, 3 equiv) in a 1:1 mixture of isopropanol and deionized water (3.2 mL). p-toluenesulfonic acid monohydrate was added (500 mg, 2.6 mmol, 1.1 equiv) before the introduction of a solution of (E)-N-(2-chloropyrimidin-4-yl)-N-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)-4methylbenzenesulfonamide 2b (840 mg, 2.4 mmol, 1 equiv) in isopropanol (9 mL). The reflux was kept for 7 h before cooling down the resulting mixture. Water was added and the desired product was extracted with ethyl acetate and washed with a saturated solution of sodium hydrogen carbonate, followed by brine. Organics were dried over anhydrous sodium sulfate and concentrated down. Trituration in acetone of the resulting crude solid yielded the desired compound (562 mg, 45%).

[0166] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm)=8.17 (d, J=5.8 Hz, 1H), 7.99-7.94 (m, 2H), 7.58-7.54 (m, 2H), 7.51-7.47 (m, 2H), 7.44-7.37 (m, 2H), 7.27 (d, J=8.8 Hz, 4H), 6.19 (d, J=5.8 Hz, 1H), 5.95 (d, J=16.6 Hz, 1H), 2.43 (s, 3H), 2.10 (s, 7H).

[0167] .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm)=159.8, 159.0, 158.5, 149.4, 145.5, 143.3, 140.3, 138.0, 136.7, 134.4, 133.2, 129.7, 129.2, 128.1, 119.4, 118.9, 117.9, 105.2, 100.7, 98.2, 21.8, 19.1.

[0168] MS (ESI) m/z=521.1 (M+H).sup.+

[0169] Synthesis of 4-[(4-{4-[(E)-2-cyanoethenyl]-2,6-dimethylanilino}pyrimidin-2-yl)amino]benzonitrile hydrochloride (Rilpivirine hydrochloride).

##STR00029##

[0170] In a reaction vial were mixed methyl (E)-N-(2-((4-cyanophenyl)amino)pyrimidin-4-yl)-N-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)-4-methylbenzenesulfonamide 3b (156 mg, 0.3 mmol, 1 equiv) and zinc dust (106 mg, 3 mmol, 10 equiv) in acetic acid (3 mL). The reaction mixture was heated at 100° C. for 1 h. TLC showed incomplete conversion, thus zinc dust (106 mg, 3 mmol, 10 equiv) was added and the mixture was stirred at 100° C. for another 30 min. Water was then added and the mixture was extracted with ethyl acetate. Organics were washed with a saturated aqueous solution of sodium hydrogen carbonate before being dried over anhydrous sodium sulfate and evaporated. The crude mixture was then dissolved in boiling isopropanol (9 mL) and 37% aqueous hydrochloric acid was added (25 μL, 0.3 mmol, 1 equiv). The mixture was cooled down, and the desired Rilpivirine hydrochloride was collected by filtration (61 mg, 50%).

[0171] .sup.1H, .sup.13C NMR and MS matched the analytical reference.

Example 4

[0172] ##STR00030##

[0173] Synthesis of (E)-N-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)methanesulfonamide 1c

##STR00031##

[0174] In a round bottom flask under nitrogen were mixed (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile (1.0 g, 6.0 mmol, 1.0 equiv) and pyridine (956 μL, 12 mmol, 2.0 equiv) in dry dichloromethane (20 mL). The mixture was cooled to 0° C. before the dropwise addition of methanesulfonyl chloride (927 μL, 12 mmol, 2.0 equiv). The reaction was allowed to warm up to room temperature and stirred for 48 h. The mixture was then washed with a 1 M aqueous solution of hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and finally water before drying the organic layer over anhydrous sodium sulfate and concentration. The crude solid was recrystallized from a mixture of petroleum ether and ethyl acetate to give the desired compound as a brown solid (895 mg, 60%).

[0175] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm)=7.31 (d, J=16.6 Hz, 1H), 7.20 (br. s, 2H), 5.99 (br. s, 1H), 5.85 (d, J=16.6 Hz, 1H), 3.13 (s, 3H), 2.44 (s, 6H).

[0176] .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm)=149.7, 138.2, 135.7, 133.0, 127.9, 118.1, 97.2, 42.4, 19.5.

[0177] MS (ESI) m/z=249.0 (M−H).sup.−

[0178] Synthesis of (E)-N-(2-chloropyrimidin-4-yl)-N-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)methanesulfonamide 2c

##STR00032##

[0179] In a reaction vial under nitrogen, was dissolved sodium tert-amylate (36 mg, 3.6 mmol, 1.2 equiv) in dry dimethylsulfoxide (1.6 mL). The resulting mixture was stirred for 1 h until a clear solution was obtained before the dropwise addition of a solution (E)-N-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)methanesulfonamide 2b (750 mg, 3 mmol, 1 equiv) in dry dimethylsulfoxide (1.6 mL). The stirring was continued for 1 h before its dropwise transfer to a solution of 2,4-dichloropyrimidine (582 mg, 3.9 mmol, 1.3 equiv) in dry dimethylsulfoxide (1.5 mL). After 1 h, the mixture was diluted with brine and extracted with ethyl acetate. Organics were dried over anhydrous sodium sulfate and concentrated down. The desired compound was obtained after recrystallization of the crude material from a mixture of petroleum ether and ethyl acetate (710 mg, 65%).

[0180] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm)=8.27 (d, J=5.8 Hz, 1H), 7.35 (d, J=16.7 Hz, 1H), 7.32-7.29 (m, 2H), 5.98 (d, J=5.7 Hz, 1H), 5.92 (d, J=16.6 Hz, 1H), 3.75 (s, 3H), 2.26 (s, 6H).

[0181] .sup.13C NMR (101 MHz, CDCl.sub.3) δ (ppm)=160.9, 160.4, 160.2, 149.1, 139.6, 136.0, 135.0, 128.4, 117.7, 105.3, 98.6, 44.6, 18.9.

[0182] MS (ESI) m/z=363.0 (M+H).sup.+

[0183] Synthesis of (E)-N-(2-((4-cyanophenyl)amino)pyrimidin-4-yl)-N-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)methanesulfonamide 3c

##STR00033##

[0184] In a reaction vial were heated to reflux a mixture of 4-aminobenzonitrile (588 mg, 5.0 mmol, 3 equiv) in a 1:1 mixture of acetic acid and deionized water (2 mL). 37% hydrochloric acid in water was added (160 μL, 2.0 mmol, 1.2 equiv) before the introduction of a solution of (E)-N-(2-chloropyrimidin-4-yl)-N-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)methanesulfonamide 2c (600 mg, 1.7 mmol, 1 equiv) in acetic acid (6 mL). The reflux was kept for one hour before cooling down the resulting mixture. Water was added and the desired product precipitated. The crude solid was then dissolved in ethyl acetate and washed with a saturated solution of sodium hydrogen carbonate, followed by brine. Organics were dried over anhydrous sodium sulfate and concentrated down to give the desired product (570 mg, 77%).

[0185] .sup.1H NMR (400 MHz, CDCl3) δ (ppm)=8.17 (d, J=5.7 Hz, 1H), 7.88 (br. s, 1H), 7.83-7.78 (m, 2H), 7.65-7.59 (m, 2H), 7.37 (d, J=16.7 Hz, 1H), 7.30 (s, 2H), 5.93 (d, J=16.6 Hz, 1H), 5.65 (d, J=5.7 Hz, 1H), 3.63 (s, 3H), 2.29 (s, 6H).

[0186] .sup.13C NMR (101 MHz, CDCl3) δ (ppm)=160.0, 159.5, 158.4, 149.3, 143.2, 139.8, 136.7, 134.8, 133.4, 128.3, 119.3, 119.3, 117.9, 105.5, 99.4, 98.4, 44.0, 18.9.

[0187] MS (ESI) m/z=445.1 (M+H).sup.+

[0188] Synthesis of 4-[(4-{4-[(E)-2-cyanoethenyl]-2,6-dimethylanilino}pyrimidin-2-yl)amino]benzonitrile hydrochloride (Rilpivirine hydrochloride).

##STR00034##

[0189] In a round bottom flask were mixed (E)-N-(2-((4-cyanophenyl)amino)pyrimidin-4-yl)-N-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)methanesulfonamide 3c (133 mg, 0.3 mmol, 1 equiv) and potassium carbonate (330 mg, 2.4 mmol, 8 equiv) in DMF (3 mL). The reaction mixture was heated at 80° C. for 48 h. Water was then added and the mixture was extracted with ethyl acetate. Organics were washed with brine before being dried over anhydrous sodium sulfate and evaporated. The crude mixture was then dissolved in boiling isopropanol (12 mL) and 37% aqueous hydrochloric acid was added (25 μL, 0.3 mmol, 1 equiv). The mixture was cooled down, and the desired Rilpivirine hydrochloride was collected by filtration (71 mg, 59%).

[0190] .sup.1H, .sup.13C NMR and MS matched the analytical reference.