A three-level face-centered central composite experimental design was applied to the reaction parameters (concentration, stoichiometry, temperature) of an acid-catalyzed rearrangement of a morphine derivative, with the aim of reducing the very dilute workup procedure required for isolation of the aporphine product without compromising yield, quality, or other parameters. This enabled the concentration of starting material in the acid catalyst to be increased 2-fold while maintaining other parameters, resulting in nearly 60% overall volume reduction on workup. This formal experimental design study required only 17 tube-scale experiments, yielding a more robust process overall, and additionally provided a greater understanding of the reaction design space for potential future scale-up.

A new strategy to identify, assess, and mitigate the nitrosamine formation in APIs during storage was developed and demonstrated on sitagliptin hydrochloride monohydrate, in which an increase in nitrosamine content was observed during stability studies. Comprehensive stress tests and stability assessments were carried out to evaluate the influence of various internal and external stimuli. Air exposure, secondary amine content, and optimum pH conditions emerged as the principal trigger factors. The results were consistent across all four distinct types of sitagliptin hydrochloride monohydrate tested, which were synthesized at different manufacturing sites and via diverse synthetic routes. A mitigation strategy was developed in which the secondary packaging material was modified to effectively prevent the ingress of air. This change yielded a clear reduction in nitrosamine formation, confirmed by 6-month stability studies at 40 °C.

Spiro[3,7-diazabicyclo [3.3.1] nonane-9,1′-cyclohexane]-2,4,6,8-tetrone (8) is an important intermediate that opens up two distinct synthetic pathways for the production of gabapentin and bispidine. This work describes the acidic hydrolysis of 2,4-dioxo-3-azaspiro-1,5-dicarbonitrile (7) to obtain (8) and investigates the effect of the most important variables on its yield percentage. Box–Behnken design (BBD) as a subclass of response surface methodology (RSM) was conducted to explore the most suitable operating conditions for maximizing the yield of the product (8) and reducing the formation of the impurities. The effective factors in this process were the H2SO4 concentration (X1), reaction temperature (X2), and reaction time (X3). The optimal reaction conditions of 65.5% sulfuric acid concentration, 22 h time, and 102 °C temperature were obtained, corresponding to the maximum reaction yield. Under these conditions, the experimental yield was 89.25 ± 1.31%, which was matched with the predicted yield (90.03%). The yield of the reaction was significantly higher than that reported in most published studies, and the impurity formation reached a minimum. The optimization results showed that the reaction yield decreased at both low and high temperatures (as well as the acid concentration) owing to a lack of reaction progress and the formation of impurities. However, in the given time frame (19–24 h), the impact of the time on the reaction efficiency was not as strong as that for the other two factors, despite being significant. In addition,13C and 1H NMR analyses revealed that the formation of 2,4-dioxo-3-azaspiro[5.5]undecane-1-carboxamide (13) and 1,1-cyclohexanediacetic acid (CDA)(14) was minimized.

We describe herein the process development and scale-up of a complex cyclopropyl pyrazole fragment of lenacapavir, a drug recently approved for long-acting treatment of HIV (Sunlenca). A ten-step asymmetric synthesis was developed utilizing simple starting materials capable of supporting the commercial supply chain of lenacapavir. Key aspects of this development effort were the oxidation strategy to elaborate the core and optimization of the fluorination reaction to afford the final product.

This position study provides a science-based, holistic approach to evaluating the risks of nitrosamine presence in drug-linkers as intermediates toward antibody–drug conjugate (ADC) drug substances. The evaluation of 47 different ADC drug substances, which have a recommended dose available in the public domain, supports the conclusion that the chemically synthesized fragments of ADCs are unlikely to lead to nitrosamine presence in the final drug product. Hence, it can be concluded that for most ADCs there are few nitrosamine risks introduced by the drug-linkers and their impurities. An abbreviated workflow for quality risk management of nitrosamine in drug-linkers is therefore proposed.

Bruton’s tyrosine kinase (BTK) is involved in B-cell receptor signaling and has been clinically validated as a target by small molecule inhibition for the treatment of a variety of cancers. ABBV-992 (1) was identified as a novel, potent, selective BTK inhibitor and advanced to Phase I clinical trials. An enantioselective synthesis of 1 was developed and scaled to provide 63 g for preclinical characterization. The route features a diazotization enabled by flow chemistry, a novel, selective partial reduction of a pyridone, a stereoselective Ellman imine reduction, and an improved acrylamide formation using 3-chloropropionyl chloride in a masked acrylate strategy.

Oligomeric proanthocyanidins (OPCs) have a variety of biological functions, but the formation of 4,8-interflavan bonds faces scaling-up difficulties due to the challenging control of stereoselectivity and the degree of polymerization. Here we report a process to produce procyanidin B3 (1) by mainly optimizing the condensation reaction and improving benzylation, C4 activation, and one-pot hydrogenolysis reactions. In an optimized seven-step process, the product 1 was achieved by only one-step chromatography in the case of poor crystallinity of polyphenols. This strategy provided effective access to the stereoselective synthesis of the title compound and other C4–C8 connected OPCs.

Bromoacetamide 1 is a phosphorylated glucocorticoid drug-linker used in conjugation with the monoclonal antibody (mAb) adalimumab to produce the antibody-drug conjugate ABBV-154. A scalable route to drug-linker 1 has been developed that improves upon the first-generation sequence and allows the production of hundreds of grams of material. The new route begins with an acetal formation that incorporates a crystallization eliminating the previous need for reversed-phase chromatography to reject the undesired acetal diastereomer. The dipeptide portion of the linker fragment is then installed in a single transformation. The subsequent product is taken directly into a phosphorylation using a one-pot phosphoramidite displacement and oxidation sequence. Deprotection of a Fmoc group is accompanied by a continuous extraction to remove associated byproducts. The amine is coupled with bromoacetic acid, and a final global deprotection of three t-butyl groups with a reversed-phase purification yields drug-linker.

In this article, a novel and practical approach was presented for the synthesis of deoxycholic acid (1) from cholic acid (2). The synthesis pathway involved the obtention of acid (20) from compound 2 via selective oxidation, followed by the condensation of 20 with p-toluenesulfonylhydrazine (23) to form hydrazones (21). Subsequently, product 1 was generated through a three-step reaction process involving reduction by NaBH4. The overall yield achieved 62.9%, with an HPLC purity of 100.00%. Structural confirmation of all compounds was performed using 1H NMR and 13C NMR spectroscopy as well as HRMS.

A new synthesis of tert-butyl (1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexylcarbamate, a key intermediate of edoxaban, is disclosed. This compound is a cyclohexane cis-diamine whose structure is a synthetic challenge. The known synthetic methods suffer from drawbacks, such as low yield, long reaction times, as well as excessive use of NaN3. The new method includes a total of nine steps starting from the known compound, (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one, whose γ-butyrolactone frame is ring-opened to form trans-3-azido-4-hydroxy cyclohexane after the first two steps. Subsequent oxidation leads to the formation of a cyclohexanone, which is then transformed to cis-diamine through enzyme-catalyzed asymmetric reductive amination, acylation with CbzCl, and reduction of the azido group successively. The target, tert-butyl (1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexylcarbamate, is finally formed through acylation with (Boc)2O, followed by deprotection of the Cbz group using hydrogenation.