The development of an effective synthetic route of lesinurad (RDEA594)

Background Lesinurad is a novel selective uric acid salt transport protein 1 (URAT1) inhibitor which is approved in the USA for the treatment of gout. However, there are some shortcomings among the reported synthetic routes, such as expensive materials, environmental pollution and poor yield. Results In this study, an efficient, practical and environmentally-friendly synthetic route of lesinurad is reported. The main advantages of this route include inexpensive starting materials, mild conditions and acceptable overall yield (38.8%). Conclusion Generally, this procedure is reasonable, reliable and suitable for industrial production.Graphical abstract The improved synthetic procedure of lesinurad (I). Electronic supplementary material The online version of this article (doi:10.1186/s13065-017-0316-y) contains supplementary material, which is available to authorized users.


Background
Gout is a worldwide severe disease and affects millions of people especially in adult men. It is a crystal correlation arthropathy resulting from crystallization and deposition of monosodium urate (MSU), and is related to the purine metabolic disorder and the reduction of uric acid excretion. Sustained hyperuricemia is the most important biochemical basis of gout: normal adults produce about 750 mg of uric acid every day, of which approximately two-thirds of total urate is endogenous, while the remaining is from dietary purines. Irregular metabolism and decomposition can destroy the stability of uric acid level in the body and therefore result in hyperuricemia and gout. The population of gout patients has been rapidly increasing over the decades, while the existing drugs are limited. In this way, new treatment for hyperuricemia and gout is imperative [1][2][3][4][5][6].
In Scheme 1, some limitations rendered this synthetic route unsuitable for larger-scale deliveries. (1) The low overall yield over the eight steps (just 9.5%) was not viable for a long-term synthesis; (2) in the first step, the reaction requires relatively harsh conditions (anhydrous oxygen free condition) and higher requirement for equipment; (3) the expensive starting material and the catalyst [1,3-bis(diphenylphosphino)propane]nickel(II) chloride were introduced at an early stage of the synthesis; (4) what is more, the use of extremely toxic, cacodorous and non-environmental-friendly reagent thiophosgene is highly undesirable for large-scale industrialization [16][17][18].
In another synthetic route (Scheme 2), the synthesis work started with the commercially available 5. After esterification, bromination and hydrolysis, lesinurad (I) was finally obtained. Compared with the synthesis route in Scheme 1, there are no obvious advantages for this one [19].
In Schemes 3 and 4, the starting material 6 was treated in two different ways [16,20]. However, both two routes are not practically valuable because of the commercially unavailable starting material, the long reaction time and low overall yield [20].
Therefore, these drawbacks prompted us to consider some alternative approaches to synthesize lesinurad  [16][17][18] Scheme 2 Synthesis of lesinurad (I) with 5 as starting material [19] and its intermediates. Herein, we present our efforts for the development of an efficient synthetic route with increased overall yield and reasonable reaction time. Results related to this work are summarized in this manuscript.
Comparing with the synthetic route in Scheme 1, we use 4-bromonaphthalen-1-amine as the starting material instead of unstable reagents such as cyclopropylmagnesium. Moreover, the route procedures are greatly shortened and improved. 1-Cyclopropyl-4-isothiocyanatonaphthalene (5) is an essential intermediate in the synthetic route of lesinurad (I), while thiophosgene was utilized to afford the key intermediate 5 in the previously reported synthetic routes. As is well known, thiophosgene is a reagent with low boiling point, volatility, smelly odor and strong toxicity. It is difficult to maintain a fully closed atmosphere during industrial production, and in Scheme 3 Synthesis of lesinurad (I) with 6 as starting material [16] Scheme 4 Alternative synthesis of lesinurad (I) with 6 as intermediate [20] this step, the actual amount of thiophosgene should be up to 2-3 times more than the theoretical amount, resulting in serious environmental pollution. In addition, when thiophosgene was employed to obtain the key intermediate 5, some by-products also emerged, such as thiourea and its derivatives, which brought difficulties for separation and purification [21].
To begin with, 1,1′-thiocarbonyldiimidazole (TCDI) was selected as an alternative reagent to replace thiophosgene. The effects of different temperature (microwave, or not), reaction solvents (DMF, 1,4-dioxane, THF and dichloromethane) on the yields of product were analyzed. The results were depicted in Table 1.
The common solvent DCM with lower boiling point was firstly applied at room temperature (25 °C) (entry 1-3). Obviously, the high yielding reaction time was 12 h (83.6%). Then THF and DMF with higher boiling point were utilized as solvents to perform this reaction under room temperature and 120 °C, respectively (entry 4-7). Compared with DCM, the yield was not increased in THF and DMF at room temperature. Higher temperature seemed to be detrimental to the yield. Unfortunately, the use of microwave radiation instrument in relatively short time and higher temperature didn't have a beneficial effect on this reaction.
Then, we discuss the proper ratio between 4-cyclopropylnaphthalen-1-amine and TCDI (Table 2). We change the amount of TCDI to find the best scale. Obviously, the high yielding reaction ratio was 4-cyclopropylnaphthalen-1-amine/TCDI = 1:1.5. All in all, the optimum (high yielding) conditions for this study are as follows: the temperature of reaction is about 25 °C, the proper reaction time is 12 h, the solvent is DCM and the suitable ratio between 4-cyclopropylnaphthalen-1-amine and TCDI is 1:1.5.

Conclusions
In conclusion, we provide an alternative method for the preparation of lesinurad, a newly-launched medicine for the treatment of gout. The method proceeds in six linear steps on gram scale with multiple advantages, including higher total yield of 38.8% (much better than those of the original ones). The most significant step of the route is the synthesis of key intermediate 1-cyclopropyl-4-isothiocyanatonaphthalene (5), and the main advantages of the method are readily available inexpensive starting materials, less toxic condition and high yield. Importantly, the reaction reactant, solvent, reaction time and temperature of this step were preliminarily investigated. This efficient and environmental-friendly process and the optimum conditions for the preparation of lesinurad may form the basis of a future manufacturing route. Further work in our lab would be required to remove the requirement for a silica treatment and then to perform a scale-up campaign (Additional file 1).

Experimental section
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-d 6 . 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). 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 instrument. Solvents were of reagent grade and, if needed, were purified and dried by distillation. Starting materials, solvents, and the key reagents were purchased from commercial suppliers and were used as received without purification.
Rotary evaporators were served in concentration of the reaction solutions under reduced pressure.