General and Scalable Synthesis of 2-Aryl and 2-Alkyl Pyrimidines via an Electronically Tuned SNAr Approach.

An efficient SNAr approach for generating a wide array of 2-aryl and 2-alkyl pyrimidines in good to high yields was developed. This methodology does not require precious metal catalysts and is compatible with aryl, heteroaryl, and alkyl magnesium halides as nucleophiles. This process is scalable and performed at room temperature well below the temperature of the competing decomposition of the activated 2-tert-butyl sulfonyl pyrimidine electrophile.

Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19.

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.

Amide-Assisted Hydrolysis of beta-Carboxamido-Substituted Phosphinic Acid Esters.

Phosphinic acids are of interest due to their ability to inhibit metalloproteases. The hydrolysis of a phosphinic acid ester is typically one of the final steps in the synthesis of such inhibitors. We have found that the acid-catalyzed hydrolysis of a phosphinic acid ester containing a beta-carboxamido group is facilitated by the presence of the amide. The promotion of the hydrolysis is dependent on the electron density of the amide suggesting the intermediacy of a cyclic imidate structure (C). The hydrolysis of phosphinic acid esters containing a beta-carboxamido group is conveniently and quantitatively effected by treating the ester with 10:90 H(2)O:TFA.

DBU catalysis of N,N'-carbonyldiimidazole-mediated amidations.

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has been found to catalyze the amidation of acyl imidazoles. The rate acceleration is especially evident with traditionally unreactive, electron-deficient anilines. DBU is readily available and offers safety and cost advantages over more commonly employed catalysts such as 1-hydroxybenzotriazole.

Iliohypogastric-ilioinguinal peripheral nerve block for post-Cesarean delivery analgesia decreases morphine use but not opioid-related side effects.

PURPOSE: To examine if ilioinguinal-iliohypogastric nerve block could reduce the need for post-Cesarean delivery morphine analgesia and thus reduce the incidence of opioid related adverse-effects. METHODS: A multi-level technique for performing the nerve block with bupivacaine was developed and then utilized in this two-part study. Part one was a retrospective assessment of Cesarean delivery patients with and without ilioinguinal-iliohypogastric blocks to determine if the technique reduced patient controlled analgesia morphine use and thus would warrant further study. The second phase was a randomized double-blind placebo-controlled trial to compare post-Cesarean morphine use and the appearance of opioid-related side effects between the anesthetic and placebo-injected groups. RESULTS: Both phases demonstrated that our method of ilioinguinal-iliohypogastric nerve block significantly reduced the amount of iv morphine used by patients during the 24 hr following Cesarean delivery. In the retrospective assessment, morphine use was 49 +/- 30 mg in the block group vs 79 +/- 25 mg in the no block group (P = 0.0063). For the prospective trial, patients who received nerve blocks with bupivacaine had a similar result, self-administering 48 +/- 27 mg of morphine over 24 hr compared to 67 +/- 28 mg administered by patients who received infiltrations of saline. However, despite the significant decrease in morphine use, there was no reduction in opioid-related adverse effects: the incidences of nausea were 41% and 46% (P = 0.70) and for itching were 79% and 63% (P = 0.25) in the placebo and nerve block groups, respectively. CONCLUSION: A multi-level ilioinguinal-iliohypogastric nerve block technique can reduce the amount of systemic morphine required to control post-Cesarean delivery pain but this reduction was not associated with a reduction of opioid related adverse effects in our study group.