Furan-Terminated N-Acyliminium Ion Initiated Cyclizations in Alkaloid Synthesis.

A study of the utility of furan-terminated N-acyliminium ion initiated cyclizations for the synthesis of linearly fused alkaloid precursors (Figure 2) is presented. The outcome of the cyclization event depends on the position of furan tether attachment (2 vs 3), tether length, and furan 5-substituent (R = H, CH(3), Ar). 3-Substituted furans cyclized to form 6- and 7-membered ring containing furans 35-38, 50, and 51 in good to excellent yields. 2-Substituted furans closed to form only 6-membered rings; however, the products obtained were a function of the furan 5-substituent. The 5-H furans 17 and 18 led exclusively to the corresponding furans 21 and 22, while the 5-CH(3)-furans 42 and 43 gave only diketone containing compounds 44 and 45. 5-Arylfurans 66-71 provided mixtures of furan- and diketone-containing products 72-83, with the ratio related to the substitution on the phenyl moiety. A preparation of epilupinine 10 is also discussed.

Pharmaceutical impurity identification: a case study using a multidisciplinary approach.

A multidisciplinary team approach to identify pharmaceutical impurities is presented in this article. It includes a representative example of the methodology. The first step is to analyze the sample by LC-MS. If the structure of the unknown impurity cannot be conclusively determined by LC-MS, LC-NMR is employed. If the sample is unsuitable for LC-NMR, the impurity needs to be isolated for conventional NMR characterization. Although the technique of choice for isolation is preparative HPLC, enrichment is often necessary to improve preparative efficiency. One such technique is solid-phase extraction. For complete verification, synthesis may be necessary to compare spectroscopic characteristics to those observed in the original sample. Although not widely practiced, an effective means of getting valuable structural information is to conduct a degradation study on the purified impurity itself. This systematic strategy was successfully applied to the identification of an impurity in the active pharmaceutical ingredient 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulphonylurea. Identification required the use of all of the previously mentioned techniques. The instability of the impurity under acidic chromatographic conditions presented an additional challenge to purification and identification. However, we turned this acidic instability to an advantage, conducting a degradation study of the impurity, which provided extensive and useful information about its structure. The following discussion describes how the information gained from each analytical technique was brought together in a complementary fashion to elucidate a final structure.

Discovery of two clinical histamine H(3) receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764).

The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.