In collaboration with Anacor and the Drugs for Neglected Diseases Initiative (DNDi), SCYNEXIS recently discovered SCYX-7158 (1), a novel representative of the oxaborole class of compounds with excellent activity against Human African Trypanosomiasis (HAT) or “sleeping sickness”. HAT is a devastating disease that threatens more than 60 million people in sub-Saharan Africa [1]. The discovery eff orts leading to 1 have been well documented [2] and describe the attractive biological, pharmacokinetic and pharmacodynamic properties this unique molecule off ers. While the initial medicinal chemistry synthesis (Scheme 1) was adequate for preparation of analogs and investigational biological studies, it was not suitable to provide the quantities of material necessary to support IND-enabling safety studies or clinical development. Once ‘7158 was confi rmed as a pre-clinical candidate, development of a scalable synthesis route became a necessity. The route would have to be cost eff ective and safe, as well as control purity, color and polymorph of the API.
Scheme 1 – Medicinal Chemistry Synthesis of SCYX-7158While the original route was eff ective for producing multi-gram quantities of the API, it was not amenable to scale-up. The route started with 2, a relatively expensive aryl boronic acid. This was protected as borocan 3 and halogen-lithium exchange followed by reaction with acetone and subsequent deprotection provided the oxaborole 4. This protection/alkylation/deprotection sequence added two steps to the overall synthesis and the metalation was not reliable. However, the biggest concern in the sequence was nitration of 4 to give 5. This was accomplished by adding a concentrated solution of 4 to cold fuming nitric acid. Besides the signifi cant safety considerations, the reaction did not scale well. Reduction of the nitro group to give aniline 6 was followed by amide formation to provide 1. While this end game was effi cient, the material produced was dark in color. The colored impurities were not removed by crystallization of 1 and furthermore a mixture of two polymorphs was formed under the original conditions.
The process chemistry route to SCYX-7158 is shown in Scheme 2. When considering alternative routes to 1, the readily available and inexpensive methyl 2-bromobenzoate (8) was identifi ed as an attractive starting point. Gratifyingly, treatment of 8 with methylmagnesium bromide aff orded 2-bromocumyl alcohol (9) in high yield using simple operating conditions. Lithiumhalogen exchange followed by reaction with triisopropyl borate and acidic work-up provided benzoxaborole 4, along with cumyl alcohol (10). While this conversion was not completely atom-effi cient, it was easily scalable and several strategies are available to suppress the by-product in the future.
Scheme 2 – Process Chemistry Synthesis of SCYX-7158With benzoxaborole 4 in hand, attention turned to the introduction of a nitrogen-linked amide at the C(6) position. This was accomplished using the same nitration/reduction/acylation strategy used in Scheme 1. Yet signifi cant changes to the chemistry were required for safety and reliability reasons. The fi rst task was introduction of the nitrogen. Nitration was demonstrated using acetic anhydride/nitric acid. However, due to slow rates of nitration and potential for accumulation of a reactive intermediate, alternative conditions had to be identifi ed. These limitations were overcome by use of trifl uoroacetic anhydride/nitric acid, which provided a more reactive nitrating intermediate, thus improving the rate of nitration and aff ording a process in which nitric acid was slowly added until 4 was consumed. Full safety assessment of the nitration reaction, including extensive calorimetry studies, demonstrated the safety of this reaction. This process was used to prepare kilogram quantities of 5.
Following reduction of nitrobenzoxaborole 5 to aniline 6 under standard catalytic hydrogenation conditions, acylation with 7 provided the fi nal drug candidate in high chemical yield. Two challenges remained which needed to be addressed through further optimization of the process. The fi rst challenge was color and purity of the API, which derived from a highly colored impurity generated in the nitration reaction which carried through to fi nal product and was not removed by crystallization. The second challenge was to consistently obtain a single polymorph of the API. Both challenges were addressed by isolation of crystalline isopropyl boronate 11 which rejected colored impurities, followed by regeneration of 1 through addition of water and azeotropic removal of isopropanol. This crystallization provided the API as a single polymorph. The API was isolated in good yield, very high purity and was white in color.
In conclusion, a practical route was developed for SCYX-7158 that allowed progression to human clinical trials in a timely and costeff ective manner. This drug holds promise to positively impact the lives of patients infected with sleeping sickness, a historic scourge of sub-Saharan Africa.
References
- 1986. Epidemiology and control of African trypanosomiasis. Report of a WHO expert committee. World Health Organization. Geneva, Switzerland. Technical Report Series, No. 739. 126 pp.
- Benzoxaboroles: a new class of potential drugs for human African trypanosomiasis. Robert T Jacobs, Jacob J Plattner, Bakela Nare, Stephen A Wring, Daitao Chen, Yvonne Freund, Eric G Gaukel, Matthew D Orr, Joe B Perales, Matthew Jenks, Robert A Noe, Jessica M Sligar, Yong-Kang Zhang, Cyrus J Bacchi, Nigel Yarlett, and Robert Don. Future Medicinal Chemistry. August 2011. Vol. 3, No. 10. Pages 1259-1278.
Mark S. Jensen, Ph.D., Research Investigator and Group Leader in the Process Research Department at SCYNEXIS. Dr. Jensen worked for Merck in the process research department before moving to SCYNEXIS, where he continues to design and develop novel and efficient routes to early and late stage drug candidates. These processes are used at SCYNEXIS for the production of API for clinical programs. Mark holds a Ph.D. from Oregon State University and was an NIH Postdoctoral Fellow at the University of California, Irvine.