The widespread use of amidine and guanidine bases in synthetic chemistry merits a thorough understanding of their chemical properties. The propensity of these reagents to hydrolyze under mild conditions and generate aminolactams and aminoureas, respectively, has not been adequately described previously. During the synthesis of uprifosbuvir (MK-3682), we became aware of this liability for 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) by observing the formation of an unexpected reaction impurity and traced the root cause to low levels of N-(3-aminopropyl)-ε-caprolactam present in the commercial bottle. A controlled stability study over a period of two months at 25 °C demonstrated that, above a threshold water content, DBU steadily hydrolyzed over time. Rates of hydrolysis for DBU, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 7-methyl-1,5,7triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), and N,N,N′,N′-tetramethylguanidine (TMG) in organic, aqueous, and mixed solvent systems were then measured to gain a more general appreciation of what conditions to avoid in order to maintain their integrity. Our findings indicate that these bases are hydrolytically unstable in unbuffered and very basic solutions but become significantly more stable in buffered solutions at pH values below 11.6.

The thermogravimetry (TG) results (Figure 1) for Form A were obtained at a heating rate of 10 °C/min under nitrogen atmosphere. A weight loss of 0.07% was observed up to 100.6C and 0.82% up to 254.2C . Differential scanning calorimetry (DSC) results (Figure 2) for Form A were collected at a heating rate of 10 °C/min, under nitrogen atmosphere in an open pan. No melting transition was observed.

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of...