Efficient Industrial Synthesis of the MDM2 Antagonist Idasanutlin via a Cu(I)-catalyzed [3+2] Asymmetric Cycloaddition.

A concise asymmetric synthesis has been developed to prepare idasanutlin, a small molecule MDM2 antagonist. Idasanutlin is currently being investigated as a potential treatment for various solid tumors and hematologic malignancies. The highly congested pyrrolidine core, containing four contiguous stereocenters, was constructed via a Cu(I)/(R)-BINAP catalyzed [3+2]-cycloaddition reaction. This optimized copper(I)-catalyzed process has been used to produce more than 1500 kg of idasanutlin. The manufacturing process will be described, highlighting the exceptionally selective and consistent cycloaddition/isomerization/hydrolysis sequence. The excellent yields, short cycle times and reduction in waste streams result in a sustainable production process with low environmental impact.

Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process.

The present work deals with improving the solubility of vemurafenib, a practically insoluble drug, by converting it into an amorphous-solid dispersion using a solvent-controlled precipitation process. The dispersion containing vemurafenib and hypromellose acetate succinate (HPMCAS), an enteric polymer, is termed microprecipitated bulk powder (MBP), in which the drug is uniformly dispersed within the polymeric substrate. HPMCAS was found to be the most suitable polymer for vemurafenib MBP, among a series of enteric polymers based on superior physical stability and drug-release characteristics of the MBP. The MBP provided a greater rate and extent of dissolution than crystalline drug, reaching an apparent drug concentration of 28-35 µg/mL, almost 30-fold higher than solubility of crystalline drug at 1 µg/mL. The supersaturation was also maintained for more than 4 h. Upon exposure to high temperature and humidity, the MBP was destabilized, resulting in crystallization and lower dissolution rate. The control of moisture and temperature is essential to maintain the stability of the MBP. In a relative human bioavailability study, vemurafenib MBP provided a four- to fivefold increase in exposure compared with crystalline drug. Improving solubility with an amorphous-solid dispersion is a viable strategy for the development of practically insoluble compounds.

The Coordination Chemistry of Fluorocarbons: Difluoro-m-cyclophane-Based Fluorocryptands and Their Group I and II Metal Ion Complexes.

The reactions of 1,3-bis(bromomethyl)-2-fluorobenzene with the bis(trifluoroacetamides) of 1,3-bis(aminomethyl)-2-fluorobenzene and 1,3-bis(aminomethyl)benzene yield the respective 1+1-condensed [3.3]-m-cyclophanes, respectively termed F(2)-phane (yield 39%) and HF-phane (yield 48%) without trifluoroacetamide groups. The reactions of F(2)-phane with 1,8-diiodo-3,6-dioxaoctane and 1,11-diiodo-3,6,9-trioxaundecane result in the respective 1+1-addition products 1,10-diaza-25,26-difluoro-4,7-dioxatetracyclo[8.7.7.1(12,16).1(19,23)]hexaeicosa-12,14,16(25),19,21,23(26)-hexene (= F(2)-[2.1.1]-cryptand) (yield 5%) and 1,13-diaza-28,29-difluoro-4,7,10-trioxatetracyclo[11.7.7.1(15,19).1(22,26)]nonaeicosa-15,17,19(28),22,24,26(29)-hexene (= F(2)-[3.1.1]-cryptand) (yield 39%). Analogous reactions of the HF-phane give the related macrocycles HF-[2.1.1]-cryptand (yield 68%) and HF-[3.1.1]-cryptand (yield 76%). The coordination of alkali and alkaline earth metal ions by these fluorophane cryptands results in significant shifts of the (19)F NMR resonances: F(2)-[2.1.1]-cryptand, delta -100.70 ppm; its Li(+) complex, delta -129.23 ppm. The (1)J(CF) coupling constant for such complexes is correlated with the degree of interaction between CF units and metal ions, and the most pronounced decrease (262 Hz to 232 Hz) is found for the lithium complex of the F(2)-[2.1.1]-cryptand. Competition experiments show the difluoro F(2)-[3.1.1]-cryptand to form significantly stronger complexes with Na(+) than the monofluoro HF-[3.1.1]-cryptand. In the crystal structure of F(2)-[2.1.1]-cryptand.NaCF(3)SO(3), the sodium ion displays an unusual F(2)O(4)N coordination sphere with extremely short sodium-fluorine distances: CF.Na(+) = 229.8(3), 235.7(4) pm; O-Na(+) = 228.5(4), 242.0(4), 243.8(4), 247.6(4) pm; N-Na(+) = 285.1(7) pm. In the closely related crystal structure of HF-[3.1.1]-cryptand.NaClO(4), the metal has an FO(5)N coordination sphere: CF.Na(+) = 236.0(4) pm; O-Na(+) = 234.8(6), 239.3(6), 240.3(12), 240.6(6), 285.7(17) pm; N-Na(+) = 272.3(6) pm. In the crystal structure of F(2)-[3.1.1]-cryptand.HCF(3)SO(3), the proton is in a pseudotetrahedral environment: N-H = 84 pm; O.HN = (216 pm; CF.HN = 224, 236 pm. This, however, is not considered indicative of significant CF.HN hydrogen bonding.