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Synthesis of Mavatrep: A Potent Antagonist of Transient Receptor Potential Vanilloid-1

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Mavatrep, a potent transient receptor potential vanilloid-1 (TRPV1) antagonist, was prepared in four steps in 63% overall yield. One of the two key synthetic transformations was the last step Suzuki coupling of an imidazole with an oxaborolole moiety.

Repeated attempts to carry out the Suzuki coupling reaction under the original conditions in presence of (dppf)PdCl2 as a catalyst resulted in very poor yields (5−35%) and formation of high levels of impurities requiring tedious purification. This poor outcome was even worse on larger scale.

After screening various experimental conditions, the best the best result was obtained by the use of (dtbpf)PdCl2 in DME in the presence of aqueous Na2CO3 which led to a remarkable improvement in both reaction rate and yield (scheme). The crude salt was obtained in 80−90% as a brownish solid that typically contained about 1400−1600 ppm of residual palladium. Out of the six screened SiliaMetS (Si-Diamine, Si-TAAcOH, Si-TAAcOH, Si-Thiol, Si-Thiourea and Si-Triamine), Si-Thiourea proved to be the most effective palladium scavenger.

However, an unexpected result was found by the synergistic effect of a combination of two SiliaMetS, Si-Thiol and Si-Thiourea when used in concert, which was not apparent from the screening array. Their use in combination the API with less than 10 ppm of Pd.

Wells, K. M. et al. Org. Process Res. Dev., 2015, 19, 1774 - 1783

 

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  1. SiliaMetS Thiol (SH) (R51030B)

    SiliaMetS Thiol (SH) (R51030B)

    Our most versatile and robust metal scavenger for a variety of metals under a wide range of conditions. Best scavenger for: Ag, Hg, Os, Pd & Ru. Good scavenger for: Cu, Ir, Pb, Rh, Se & Sn.
  2. SiliaMetS Thiourea (THU) (R69530B)

    SiliaMetS Thiourea (THU) (R69530B)

    SiliaMetS Thiourea (Si-THU) is a versatile metal scavenger for all forms of palladium, and is widely used in the pharmaceutical industry. Once complexed with a transition metal, it has also been reported as being an effective catalyst. Best scavenger for: Pd & Ru. Good scavenger for: Ag, Cu, Fe, Os, Rh, Sc & Sn.

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