*3.1.1.2.4 Case study* �*4: synthesis of the antiviral drug Rilpivirine hydrochloride [(Edurant®), 4-[[4-[4-[(E)-2-cyanoethenyl]-2,6-dimethylanilino]pyrimidin-2-yl]amino]benzonitrile; hydrochloride (62)]*

The non-nucleoside reverse transcriptase inhibitor (NNRTI), Rilpivirine Hydrochloride (RPV, Edurant®) (62) got the approval both from the U.S. FDA and E.U. EMA in 2011 for the treatment of HIV-1 infection in treatment-naïve adult patients (**Figure 9**) [71, 72].

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

#### **Figure 7.**

*Synthesis of Dabrafenib (GSK2118436, (60)). Reagents and conditions: a) H2SO4, MeOH; b) ArSO2Cl (43), pyridine, DCM; c) 10% Pd/C, H2, rt., 100%, d) 2-chloro-4-methylpyrimidine (61), LiHMDS, 0°C to rt., 1 h, 92%;; e) NBS, DCM then 2-aminopyridine (61), dioxane; f) NBS, DMF (or DMA) then 2,2,2 trimethylthioacetamide, rt.* ! *60°C, 1 h, 30–44%; g) 7 N ammonia in methanol, sealed tube 100°C or R2NH2 amine, HCl, 2,2,2-trifluoroethanol, microwave, 180°C.*

Structurally, the drug Rilpivirine hydrochloride (62) belongs to diarylpyrimidine (DAPY) family of compounds that re defined as the second-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs) targeting reverse transcriptase,

**Figure 8.**

*Coupling of the 2,4-disubstituted pyrimidine (60) to the sulfonamide benzoic acid ester (57). Reagents and conditions: a) 2-chloro-4-methylpyrimidine (61), LiHMDS, 0°C* ! *r.t, 1 h, 90%.*

#### **Figure 9.**

*Structures of FDA approved diarylpyrimidines (DAPYS) of pyrimidine-based non-nucleoside reverse transcriptase inhibitors (NNRTI) Rilpivirine (62) and Etravirine (63).*

playing a great irreplaceable role in HIV transcriptional therapy [73–75]. Other antiviral agents like Etravirine (63) is also defined as DAPYs and got approved by US-FDA. Some of the DAPYs also exert anticancer action [76].

A large-scale synthetic process starting from the commercially available 2-thiouracil (65) that could be converted to 2-methylthio-4-pyrimidinone (64) following methylation using methyl iodide under basic conditions (r.t., overnight, 88%) was developed. Otherwise, 2-methylthio-4-pyrimidinone (64) could be used as a starting material. The reported synthetic process comprises from 6 steps [77].

The condensation of thioether (66) with neat 4-cyanoaniline (67) at elevated temperature to afforded the substituted pyrimidone (71) in 77% yield, which upon subsequent refluxing in POCl3 provided the corresponding 4-chloropyrimidine (72) in 77% yield. 4-chloropyrimidine derivative (72) was treated with the (*E*) cinnamonitrile aniline (72) under basic conditions (K2CO3) to give rilpivirine hydrochloride (62) in good yield. The final step of amination was particularly challenging and required longer time and elevated temperatures (**Figure 10**).

(*E*)-3-(4-Amino-3,5-dimethylphenyl) acrylonitrile (73) was prepared via a Heck reaction starting from the of commercially available reagents either 4-iodo- or 4-bromo-2,6-dimethyl-benzeneamine (74) or (75) and acrylamide (76) affording compound (78) as a 4:1 mixture of *E/Z* isomers. The distribution of *E/Z* olefins was increased to 98:2 by salt formation and recrystallization to ultimately provide pure (*E*)-(62) in an overall 64% yield for the two steps. The final yield was *Synthetic Approaches for Pharmacologically Active Decorated Six-Membered Diazines DOI: http://dx.doi.org/10.5772/intechopen.109103*

**Figure 10.**

*Synthesis of 4-[(4-chloropyrimidin-2-yl)amino] benzonitrile intermediate (72) from 2-thioxo-2,3 dihydropyrimidin-4(1H)-one (65). Reagents and conditions: a) CH3I, NaOH, r.t., overnight, 88%; b) DME, reflux, 18 h, 68%; c) 180–190°C, 10 h, 70–74%; d) 180°C, 8 h, 73.6%; e) POCl3, reflux, 20 min, 77%.*

**Figure 11.**

*Synthesis of intermediate (73) from 4-bromo-2,6-dimethylaniline (74) and acrylamide (76) as starting materials [78]. Reagents and conditions: a) Pd(OAc)2, P(C6H5CH3)3, Et3N, CH3CN, N2, 79°C, overnight, 79.5%; b) POCl3, 0°C, 30 min; 20°C, overnight, 84%; c) EtOH, ((CH3)2CH2)2O, N2, 60°C, 30 min; HCl, 2-propanol, 60°C, 30 min, 77%. When starting from 4-iodo-2,6-dimethylaniline (75) and acrylonitrile, reagents and conditions: a) CH3COONa, Pd/C, DMAC, N2, 140°C, 21 h, 81%; b) EtOH, HCl, 2-propanol, 60°C, 1 h, 64.5%.*

slightly improved when 4-bromo-2,6-dimethyl-benzeneamine (74) was used compared to or 4-iodo-2,6-dimethyl-benzeneamine (75) (**Figure 11**).

The conventional way to prepare the drug Rilpivirine (62) was accomplished by nucleophically displacing the 4-chloro in 4-[(4-chloropyrimidin-2-yl)amino] benzonitrile (72) with (2*E*)-3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile hydrochloride (73). The reaction was performed in acetonitrile under reflux condition for 69 h (**Figure 12**, yield: 68.6%). Connecting the two previously prepared building blocks (72) and (73) resulted in the desired products. However, the elongated refluxing of acetonitrile resulted in extended industrial process, high demand of energy, and reduced quality and purity of the final product. Using NMP at 95°C shorten the reaction time but ended in increased ration of the *cis*-(*E*)- undesired isomer byproduct. Additionally, the high boiling point of NPM renders reclaiming the solvent in industrial process unfavorable.

**Figure 12.**

*Synthesis of Rilpivirine from intermediates (72) and (73). Reagents and conditions: a) CH3CN, reflux or NMP, 95° C, or b) microwave-irradiation, CH3CN, 140°C, 90 min, 71% [79].*

Zhang *et al* Noted four drawbacks in the traditional synthetic methods: (a) the preparation of intermediate (73) via Heck reaction turned to be expensive due to the required catalyst (palladium acetate) and its ligands; (b) the preparation of intermediate (72) is also expensive and the reaction temperature is high; (c) when using uracil as a starting material instead, the reaction process and workup was rather tedious with reduced yield and (d) the final step in the synthesis of Rilpivirine, is too long (69 h) and causing energy consumption. Due to reported shortcomings of the previously reported synthesis Zhang et al. reported an optimized conditions for the synthesis of Rilpivirine and required building blocks, 4-[(4-hydropyrimidin-2-yl) amino] benzonitrile (71) and (2*E*)-3-(4-amino-3,5-dimethylphenyl)prop-2 enenitrile hydrochloride (73) employing microwave-irradiation reaction (see below more details).

Hence there is an urgent need to find more efficient and practical methods for synthesizing Rilpivirine in the pharmaceutical industry. Herein, we represent our efforts to develop an efficient synthetic route with increased overall yield and reasonable reaction time. An alternative six-step process was proposed. The improvement was primarily in preparing the intermediate (64) and in the conditions and yield on the final step. Zhang *et al* reported the solvent free fusion reaction between fusion 2-(methylthio)-4(3H)-pyrimidinone (64) and *p*-aminobenzonitrile (67) under an inert atmosphere that afforded the intermediate (72) in 70%. The intermediate 2-(methylthio)-4(3H)-pyrimidinone (64) was converted to 4 chloropyrimidine (72) form by reflux in POCl3. Though the synthesis on the second building block (intermediate (73)) was still dependent of Heck reaction conditions, the final nucleophilic step was performed under microwave-assisted conditions. After trying different solvents (dioxane, acetonitrile, and NMP) and temperatures they reported a slight improvement in the yield of the final amination product (71%) for microwave-assisted in microwave-irradiation reaction with acetonitrile solvent at 140°C for 90 min compared to (69%) via traditional method [79].

Recently, it was reported by that amination of 2-chloro-4-aryloxypyrimidines using palladium catalyzed transformation (Xantphos, Pd(AcO)2, Cs2CO3, 1.4-dioxane, reflux in N2 atmosphere, 80°C) affording the 2,4-disubtituted product (62) in 50% yield [80]. A group of aryl-2-[(4-cyanophenyl)amino]-4-pyrimidinone hydrazones reported as potent mon-nucleoside reverse transcriptase inhibitors were prepared by Ma et al. [81]. The 2-amino-hydrazone derivatives were synthesized in a yield that ranges between 40 and 50%.
