The large-scale manufacture of complex synthetic peptides is challenging due to many factors such as manufacturing risk (including failed product specifications) as well as processes that are often low in both yield and overall purity. To overcome these liabilities, a hybrid solid-phase peptide synthesis/liquid-phase peptide synthesis (SPPS/LPPS) approach was developed for the synthesis of tirzepatide. Continuous manufacturing and real-time analytical monitoring ensured the production of high-quality material, while nanofiltration provided intermediate purification without difficult precipitations. Implementation of the strategy worked very well, resulting in a robust process with high yields and purity.

Despite the benefits of high atom economy and low cost, aerobic oxidations have found limited use in the synthesis of active pharmaceutical ingredients (APIs) because of safety concerns and poor selectivity. In this report, the design, development, and scale-up of a continuous, high pressure aerobic oxidation to produce the penultimate of an API are described. The identification of robust homogeneous conditions for the oxidative C−N coupling of interest and the use of diluted air allowed for the process to be safely and selectively carried out on manufacturing scale as a continuous process using a vertical pipes-in-series reactor to prepare high-quality material.

A modular synthesis of selectively-substituted pyrrolo[2,1-b]thiazoles (D 6 isomeric form) has been implemented, involving a distinctive bicyclization reaction of a mucobromic acid derivative followed by a Suzuki-Miyaura coupling. A novel process of D 6 to D 7 isomerization of the pyrrolothiazole structure was uncovered that appears to involve a 1,4-addition-1,2-elimination mechanism. Preparation of 1,5-dihydropyrrol-2-one structures, selectively substituted at the 3-and 4-positions, was also achieved using the mucobromic acid synthon in a reductive amination process.

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Several pyrrolo[2,1‐b]thiazoles are obtained via a bicyclization reaction of mucobromic acid derivatives (III) with D‐penicillamine (IV).