The development of an effective synthetic route of rilpivirine

Abstract

Background: Rilpivirine (RPV) was approved by the U.S. FDA (Food and Drug Administration) in 2011 to treat individuals infected with human immunodeficiency virus 1 (HIV-1). Significantly, rilpivirine is three fold more potent than etravirine. Once-daily, it is used with a low oral dose (25 mg/tablet), decreasing the drug administration and bringing a better choice to the patients. However, there are many shortcomings in the existing synthesis route of RPV, such as the high cost, prolonged reaction time and low yield (18.5%).

Results: This article describes our efforts to develop an efficient and practical microwave-promoted method to synthesize rilpivirine using less toxic organic reagents and low boiling solvents. The last step's reaction time decreased from 69 h to 90 min through this optimized synthetic procedure, and the overall yield improved from 18.5 to 21%. In addition, the yield of intermediate 3 increased from 52 to 62% compared to the original patent.

Conclusion: Overall, through a series of process optimization, we have developed a practical synthesis method of rilpivirine, which is easy to scale with higher yield and shorter reaction time.

Keywords: Antiviral; HIV; Microwave-promoted method; Rilpivirine; Synthetic optimization.

Fig. 1.

The chemical structure of rilpivirine approved by the U.S. FDA in 2011

Scheme 1.

Synthesis of intermediate 2 from 5-bromo-2,4,6-trichloropyrimidine (4) and acrylamide (5) as starting materials [11]. Reagents and conditions: (i) Pd(OAc)₂, P(C₆H₅CH₃)₃, Et₃N, CH₃CN, N₂, 79 °C, overnight, 79.5%; (ii) POCl₃, 0 °C, 30 min; 20 °C, overnight, 84%; (iii) EtOH, ((CH₃)₂CH₂)₂O, N₂, 60 °C, 30 min; HCl, 2-propanol, 60 °C, 30 min, 77%

Scheme 2.

Synthesis of intermediate 2 from 4-iodo-2,6-dimethylaniline (8) and acrylonitrile (9) as starting materials [13]. Reagents and conditions: (i) CH₃COONa, Pd/C, DMAC, N₂, 140 °C, 21 h, 81%; (ii) EtOH, HCl, 2-propanol, 60 °C, 1 h, 64.5%

Scheme 3.

Synthesis of intermediate 3 from 2-thioxo-2,3-dihydropyrimidin-4(1H)-one (10) as starting material [–17]. Reagents and conditions: (i) CH₃I, NaOH, r.t., overnight, 88%; (iia) DME, reflux, 18 h, 68%; (iib) 180–190 °C, 10 h, 70–74%; (iic) 180 °C, 8 h, 73.6% (iii) POCl₃, reflux, 20 min, 77%

Scheme 4.

Synthesis of intermediate 3 from 1-(4-cyanophenyl)guanidine (14) and diethyl 2-(ethoxymethylene)malonate (15) as starting materials [18]. Reagents and conditions: (i) NMP, AcONa, 100 °C, 1 h; (ii) H₂O, 155–160 °C; AcOH, 130–150 °C, 76%; (iii) POCl₃, reflux, 20 min, 77%

Scheme 5.

Synthesis of intermediate 3 from pyrimidine-2,4(1H,3H)-dione (17) as starting material [14]. Reagents and conditions: (i) C₆H₅N(CH₃)₂, POCl₃, 0 °C; reflux, 4 h, 43%; (ii) CH₃OH, NaOCH₃, rt, 14 h, 50%; (iii) 2-Toluene sulfonic acid, dioxane, 100–110 °C, 14 h, 55%; (iv) Pyridine, 150–160 °C, 3 h, 87%; (v) POCl₃, 0 °C, reflux, 1 h, 75%

Scheme 6.

Synthesis of rilpivirine from intermediates 2 and 3 [19, 20]

Scheme 7.

The improved synthetic procedure of rilpivirine. Reagents and conditions: (i) Pd(OAc)₂, P(C₆H₅CH₃)₃, CH₃COONa, DMAC, N₂, 130 °C, 24 h, 51%; (ii) POCl₃, 40 °C 8 h; (iii) EtOH, HCl, acetyl chloride, 0 °C, 30 min, total yield of steps (ii) and (iii) 95%; (iv) N₂, 160 °C, 2 h, 180 °C, 4 h, 70%; (v) POCl₃, reflux 8 h, 89%; (vi) CH₃CN, 140 °C, 90 min, 71%