Novel eco-friendly tetramethylguanidinium propanesulfonic acid trifluoromethylacetate ([TMGHPS] [TFA]) ionic liquid was developed as catalyst and medium for the Fischer indole synthesis of a wide variety of hydrazines and ketones. The indole products were isolated in high yields and with minimal amounts of organic solvent. This reaction showed that [TMGHPS][TFA] can be regenerated and reused with reproducible yields without eroding the integrity of the ionic liquid.

The 2,2,6,6-tetramethylpiperidin-1-yloxycarbonyl (Tempoc) protecting group is readily introduced by the reaction of amines with a new acyl transfer reagent, 4nitrophenyl (2,2,6,6-tetramethylpiperidin-1-yl) carbonate (NPTC). Tempoc has a reactivity profile that complements the commonly used t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) protecting groups. Deprotection can be achieved under mild reductive conditions with in situ generated Cu(I) species or by thermolytic cleavage at 135 °C. Mechanistic studies on the deprotection of Tempoc-indole suggest a combination of ionic and radical fragmentation pathways under thermal conditions.Letter pubs.acs.org/OrgLett

IBNtxA (3-iodobenzoyl naltrexamine) is a novel μ-opioid receptor (MOR) agonist which is structurally related to the MOR antagonist naltrexone. Recent studies suggest IBNtxA preferentially signals through truncated MOR splice variants, resulting in anti-nociception with reduced side effects, including no conditioned place preference (CPP) when tested at a single dose. IBNtxA represents an intriguing lead compound for preclinical drug development targeting truncated MOR splice variants, but further evaluation of its in vivo pharmacological profile is necessary. The purpose of this study was to independently verify the antinociceptive properties of IBNtxA and to examine more completely the rewarding properties and discriminative stimulus effects of IBNtxA, allowing broader assessment of IBNtxA as a candidate for further medications development. A dose of 3 mg/kg IBNtxA was equipotent to 10 mg/kg morphine in a hot-plate analgesia assay. In drug discrimination testing using mice trained to discriminate between 3 mg/kg IBNtxA and vehicle, the κ-agonist U-50488 fully substituted for IBNtxA. MOR agonist morphine, δ-agonist SNC162, NOP agonist SCH 221510, and MOR/NOP partial agonist buprenorphine each partially substituted for IBNtxA. IBNtxA up to 3 mg/kg did not produce a place preference in CPP. Pretreatment with 3 mg/kg IBNtxA but not 1 mg/kg IBNtxA attenuated acquisition of place preference for 10 mg/kg morphine. A dose of 3 mg/kg IBNtxA attenuated morphine-induced hyperlocomotion but did not alter naloxone-precipitated morphine withdrawal. Overall, IBNtxA has a complicated opioid receptor pharmacology in vivo. These results indicate that IBNtxA produces potent anti-nociception and has low abuse liability, likely driven by substantial κ agonist signaling effects.

MRTX0902, a novel SOS1 inhibitor, is currently being evaluated in phase I trials for the treatment of cancer. The complexity of the molecule, which contains a pyrido [3,4-d]pyridazine core and a chiral amine moiety, makes it a challenging target to prepare on a multi-kilogram scale to support clinical development studies. An efficient and scalable synthesis of the key intermediate 4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1(2H)-one and a much improved end-game for MRTX0902 were developed.

The “butterfly-shaped” bicyclic pyrrolidinol ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a­(5H)-yl)-methanol (1) is a key building block for drug candidates, and its practical chemical synthesis remains elusive. As such, an asymmetric synthesis for ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a­(5H)-yl)-methanol (1) that is amenable for scale-up has been developed. The newly optimized process utilizes readily available N-Boc-trans-4-hydroxy-l-proline methyl ester (8) to establish the challenging stereogenic center bearing the fluoride. Subsequent diastereoselective α-alkylation was achieved by leveraging Seebach’s self-regeneration of stereochemistry (SRS) methodology, which has been exploited for the synthesis of proline derivatives. Finally, intramolecular cyclization/deprotection cascade and carbonyl reduction afford the bicyclic pyrrolidinol 1 in nine linear steps from compound 8. This process significantly reduces the overall production sequence and allows the preparation of product 1 on a multikilo scale with a 40% overall yield and perfect control of chirality (>99% ee and de).