An improved synthesis approach of the HIV-1 inhibitor RDEA427, a pyrrolo[2,3-d ]pyrimidine derivative

The diarylpyrimidine-like derivative RDEA427 is a highly potent inhibitor against wild-type and a wide range of drug-resistant HIV-1 strains and has attracted much attention. However, the yield of its reported synthesis is too low and the route is less environment-friendly and uneconomic. In order to achieve a short and more economic synthesis of RDEA427, an investigation was carried out. The optimized synthesis approach of RDEA427 was accomplished in an increased overall yield (39%). Moreover, the new route is more environment-friendly and economic. This work will accelerate the drug discovery process.

However, only one synthetic route has been disclosed in the literature till now, with a total yield less than 1.9% (Scheme 1): 9 the starting material 2,6-diamino-2,3-dihydropyrimidin-4(1H)-one (2) was condensed with chloroacetaldehyde (3) in the presence of NaOAc in water to provide the intermediate 2-amino-3,7-dihydro-4H-pyrrolo [2,3-d]pyrimidin-4-one (4).Chlorination of 4 in POCl3 using N,N-dimethylaniline and triethylbenzylammonium chloride (TEBAC) as catalysts afforded 4-chloro-7H-pyrrolo [2,3-d]pyrimidin-2-amine (5). 5 was first benzyl-protected, and then underwent a nucleophilic reaction with 4-hydroxy-3,5-dimethylbenzonitrile (7) to give intermediate 8. 8 passed through a Schiemann reaction in 60% HF-pyridine solution to supply the key intermediate 9.At last, 9 underwent another nucleophilic reaction and subsequent deprotection to afford RDEA427 (1).In the above synthesis route of RDEA427, obvious disadvantages exist as follows: 1) the overall yield is extremely low; 2) the route contains conditions under high temperature heating or rather low temperature cooling, which is very energy consuming; 3) the extremely toxic HF-pyridine solution and explosive t-butylnitrite were utilized, which was not suitable for large-scale industrialization; 4) silica gel chromatography was employed in the latter six steps to obtain the desired products, which is less environment-friendly and uneconomic for quantity production.Therefore, we became greatly interested in designing a more practical, more environment-friendly synthetic approach with improved total yield.Scheme 1. Discovery route of RDEA427 (1).

Results and Discussion
The new synthesis of RDEA427 was accomplished by a relatively more environment-friendly approach with good yields (Scheme 2).The synthesis started with the commercially available 2,4dichloro-7H-pyrrolo [2,3-d] The SEM group was then removed to give the desired product RDEA427 (1).The total yield of the new route was found to be 39%, over 20 times better than that of the original route.With the exception of the third step, the reactions conditions were relatively mild.In addition, no extremely toxic or explosive materials were utilized in the optimized route, and the silica gel chromatography was only employed in three steps, which is more economic for quantity production.

Scheme 2. The improved synthetic route of RDEA427 (1).
At first, using a protecting-group-free strategy, it was found that the starting material 12 could not directly afford RDEA427 after two-step SNAr reactions.Subsequently, (Boc)2O and ptoluenesulfonyl chloride (TsCl) were applied as possible protective agents.Unfortunately, both of the designed routes did not work out.Finally, (2-(chloromethoxy)ethyl)trimethylsilane (SEM-Cl) was adopted to achieve the aim.
Moreover, preliminary investigations were carried out to select appropriate Pd catalysts and ligands on the Buchwald-Hartwig reaction, since the third step reaction played a decisive role in improving the overall yield.Pd(OAc)2/BINAP and Pd2(dba)3/Xantphos were used with different stoichiometric ratios, and temperatures were also studied.The reaction conditions and yields were depicted in Table 1.Considering the yield, raw material price and quantity production, the condition using Pd2(dba)3 (0.015 eq)/Xantphos (0.015 eq)/80°C was ultimately employed.

Conclusions
We have developed a new synthesis approach of the HIV-1 inhibitor RDEA427.The total yield of the optimized route increased to 39%, over 20 times better than that of the original one.Protective reagents and appropriate Pd catalysts and ligands on the Buchwald-Hartwig reaction were preliminarily explored.Finally, SEM-Cl and Pd2(dba)3 (0.015 eq)/Xantphos (0.015 eq) were adopted.On the whole, the reaction conditions are relatively mild, and the new route is more environment-friendly and economic, therefore is suitable for quantity production in the future.

Experimental Section
General.All melting points (mp) were determined on a micromelting point apparatus and are uncorrected.Mass spectra were performed on a LC Autosampler Device: Standard G1313A instrument by electrospray ionization. 1 H NMR and 13 C NMR spectra were obtained on a Bruker AV-400 spectrometer (Bruker BioSpin, Fällanden, Switzerland) in the indicated solvent DMSO-d6.Chemical shifts were expressed in δ units (ppm), using TMS as an internal standard, and J values were reported in hertz (Hz).TLC was performed on Silica Gel GF254.Spots were visualized by irradiation with UV light (λ 254 nm).Flash column chromatography was carried out on columns packed with silica gel 60 (200-300 mesh).Solvents were of reagent grade and, if needed, were purified and dried by standard methods.The key reagents were purchased from commercial suppliers and with no further purification when used.Rotary evaporators were served in concentration of the reaction solutions under reduced pressure.