Thermal Ring Contraction Reactions of 9‑Aryl‑5<i>H</i>,7<i>H</i>‑[1,2,5]thiadiazolo[3,4‑<i>h</i>][2,3,4]benzothiadiazepine 6,6‑Dioxides. Experimental and Computational Studies for Understanding the Course of the Transformations

When refluxing with sodium hydrogen carbonate in acetonitrile, 7-chloro-5-(4-fluorophenyl)-1,3-dihydro-2,3,4-benzothiadiazepine 2,2-dioxide afforded, after loss of dinitrogen and subsequent ring contraction, the corresponding sulfone in 83% yield. Similar treatment of the related thiadiazolo-fused tricycles, i.e. 9-aryl-5<i>H</i>,7<i>H</i>-[1,2,5]­thiadiazolo­[3,4-<i>h</i>]­[2,3,4]­benzothiadiazepine 6,6-dioxides, resulted in a substantially different product mixture: formation of sultines and benzocyclobutenes was observed, while only small amounts of the sulfones were formed, if any. Density functional theory calculations support the mechanism proposed for the transformations involving a zwitterionic intermediate formed by the tautomerization of the thiadiazepine ring followed by dinitrogen extrusion. When starting from 7-chloro-substituted 2,3,4-benzothiadiazepine 2,2-dioxide, the formation of sulfone via <i>o</i>-quinodimethane is the preferred pathway from the zwitterion. However, in the case of thiadiazolobenzothiadiazepine 6,6-dioxides it has been found that the ring closure of the zwitterion leading to the formation of sultines was kinetically preferred over the loss of sulfur dioxide leading to <i>o</i>-quinodimethane, which is the key intermediate to benzocyclobutene-type products. The calculations explain the differences observed between the product distributions of the chloro-substituted and the thiadiazolo-fused derivatives

Application of the Systems Chemistry Approach on the Ammonolysis of 1‑Ethoxycarbonyl- and 1‑Phenoxycarbonyl-3-(2-thienyl)oxindoles. A Method to Predict Reactivity

The routine prediction of the reactivity of a complex, multifunctional molecule is a challenging and time-consuming procedure. In the last step of the synthesis of the well-known drug substance tenidap, a nonexpected difference was observed between the reactivities of two closely related carbamate moieties, the <i>N</i>-ethoxycarbonyl and the <i>N</i>-phenoxycarbonyl group. A detailed kinetic study, necessitating a significant computational effort, is described in the present paper for this reaction step. On the other hand, the systems chemistry concept, by analyzing the details of the electronic structure and the connections between functional groups in a fast and simple way, is also able to answer this question using various “-icity” parameters (aromaticity, carbonylicity, olefinicity). The complete systems chemistry approach involves all these conjugativicity parameters, while its further simplified version is based on only one key parameter, which is carbonylicity in the present case. The above methods were compared in terms of their predictive power. The results show that the systems chemistry concept, even its one-parameter version, is applicable for the characterization of this challenging reactivity issue

Thermal Ring Contraction Reactions of 9‑Aryl‑5<i>H</i>,7<i>H</i>‑[1,2,5]thiadiazolo[3,4‑<i>h</i>][2,3,4]benzothiadiazepine 6,6‑Dioxides. Experimental and Computational Studies for Understanding the Course of the Transformations

When refluxing with sodium hydrogen carbonate in acetonitrile, 7-chloro-5-(4-fluorophenyl)-1,3-dihydro-2,3,4-benzothiadiazepine 2,2-dioxide afforded, after loss of dinitrogen and subsequent ring contraction, the corresponding sulfone in 83% yield. Similar treatment of the related thiadiazolo-fused tricycles, i.e. 9-aryl-5<i>H</i>,7<i>H</i>-[1,2,5]­thiadiazolo­[3,4-<i>h</i>]­[2,3,4]­benzothiadiazepine 6,6-dioxides, resulted in a substantially different product mixture: formation of sultines and benzocyclobutenes was observed, while only small amounts of the sulfones were formed, if any. Density functional theory calculations support the mechanism proposed for the transformations involving a zwitterionic intermediate formed by the tautomerization of the thiadiazepine ring followed by dinitrogen extrusion. When starting from 7-chloro-substituted 2,3,4-benzothiadiazepine 2,2-dioxide, the formation of sulfone via <i>o</i>-quinodimethane is the preferred pathway from the zwitterion. However, in the case of thiadiazolobenzothiadiazepine 6,6-dioxides it has been found that the ring closure of the zwitterion leading to the formation of sultines was kinetically preferred over the loss of sulfur dioxide leading to <i>o</i>-quinodimethane, which is the key intermediate to benzocyclobutene-type products. The calculations explain the differences observed between the product distributions of the chloro-substituted and the thiadiazolo-fused derivatives

Thermal Ring Contraction Reactions of 9‑Aryl‑5<i>H</i>,7<i>H</i>‑[1,2,5]thiadiazolo[3,4‑<i>h</i>][2,3,4]benzothiadiazepine 6,6‑Dioxides. Experimental and Computational Studies for Understanding the Course of the Transformations

When refluxing with sodium hydrogen carbonate in acetonitrile, 7-chloro-5-(4-fluorophenyl)-1,3-dihydro-2,3,4-benzothiadiazepine 2,2-dioxide afforded, after loss of dinitrogen and subsequent ring contraction, the corresponding sulfone in 83% yield. Similar treatment of the related thiadiazolo-fused tricycles, i.e. 9-aryl-5<i>H</i>,7<i>H</i>-[1,2,5]­thiadiazolo­[3,4-<i>h</i>]­[2,3,4]­benzothiadiazepine 6,6-dioxides, resulted in a substantially different product mixture: formation of sultines and benzocyclobutenes was observed, while only small amounts of the sulfones were formed, if any. Density functional theory calculations support the mechanism proposed for the transformations involving a zwitterionic intermediate formed by the tautomerization of the thiadiazepine ring followed by dinitrogen extrusion. When starting from 7-chloro-substituted 2,3,4-benzothiadiazepine 2,2-dioxide, the formation of sulfone via <i>o</i>-quinodimethane is the preferred pathway from the zwitterion. However, in the case of thiadiazolobenzothiadiazepine 6,6-dioxides it has been found that the ring closure of the zwitterion leading to the formation of sultines was kinetically preferred over the loss of sulfur dioxide leading to <i>o</i>-quinodimethane, which is the key intermediate to benzocyclobutene-type products. The calculations explain the differences observed between the product distributions of the chloro-substituted and the thiadiazolo-fused derivatives

Thermal Ring Contraction Reactions of 9‑Aryl‑5<i>H</i>,7<i>H</i>‑[1,2,5]thiadiazolo[3,4‑<i>h</i>][2,3,4]benzothiadiazepine 6,6‑Dioxides. Experimental and Computational Studies for Understanding the Course of the Transformations

When refluxing with sodium hydrogen carbonate in acetonitrile, 7-chloro-5-(4-fluorophenyl)-1,3-dihydro-2,3,4-benzothiadiazepine 2,2-dioxide afforded, after loss of dinitrogen and subsequent ring contraction, the corresponding sulfone in 83% yield. Similar treatment of the related thiadiazolo-fused tricycles, i.e. 9-aryl-5<i>H</i>,7<i>H</i>-[1,2,5]­thiadiazolo­[3,4-<i>h</i>]­[2,3,4]­benzothiadiazepine 6,6-dioxides, resulted in a substantially different product mixture: formation of sultines and benzocyclobutenes was observed, while only small amounts of the sulfones were formed, if any. Density functional theory calculations support the mechanism proposed for the transformations involving a zwitterionic intermediate formed by the tautomerization of the thiadiazepine ring followed by dinitrogen extrusion. When starting from 7-chloro-substituted 2,3,4-benzothiadiazepine 2,2-dioxide, the formation of sulfone via <i>o</i>-quinodimethane is the preferred pathway from the zwitterion. However, in the case of thiadiazolobenzothiadiazepine 6,6-dioxides it has been found that the ring closure of the zwitterion leading to the formation of sultines was kinetically preferred over the loss of sulfur dioxide leading to <i>o</i>-quinodimethane, which is the key intermediate to benzocyclobutene-type products. The calculations explain the differences observed between the product distributions of the chloro-substituted and the thiadiazolo-fused derivatives

Dynamic Modeling and Optimal Design Space Determination of Pharmaceutical Crystallization Processes: Realizing the Synergy between Off-the-Shelf Laboratory and Industrial Scale Data

Well-designed and operated pharmaceutical crystallization can enhance the key features of the active pharmaceutical ingredients, which can be taken to the next level by a model-based design. Model development not only requires computer implementation, kinetic identification, and advanced programming skills but also a suitable number of information-rich experiments. Numerous products have been crystallized for a long time, with many related laboratory-scale experiments and plant-scale manufacturing data accumulated from past developments and productions. The question arises: can these historical data be utilized to build process models, which can be used subsequently to optimize processes? We aim to demonstrate in this study that this approach can be feasible. To illustrate this, we used the data of two commercial crystallization production campaigns, totaling 16 industrial crystallizations, and six laboratory experiments, four of which were formerly performed for different purposes. Our tailored PBM involves primary and secondary nucleation, crystal growth, and dissolution and can simultaneously reproduce laboratory- and plant-scale dynamics. Despite relying on nontargeted experiments and measuring/sampling strategy, the estimated parameters were accurate, with an average deviation between the nominal values and 95% confidence interval bonds of 16.1%. The model was employed to construct an optimal design space (DS) for a temperature cycling operation involving, as a constraint, 2, 3, and 4 cycles: the goal was to define a temperature domain with minimal batch time and heating/cooling energy demand that respects the constraints on the product PSD and heating/cooling rates. The problem was solved as a constrained robust optimization, where discrete temperature stamps and corresponding time stamps were optimized. The optimal operation halved the current batch time. The optimized temperature profile was validated on a laboratory scale for two particle size specifications. More expansive DS (1 vs 0.5 h random temperature variation allowed around the nominal temperature profile) was observed to translate to longer batch times (30 vs 25 h) and deeper temperature cycles of 40 vs 20 °C, reflecting a trade-off between nominal performance and robustness. The optimal laboratory-scale operation was validated successfully by repeated experiments

Evaluation of 3‑Ethyl-3-(phenylpiperazinylbutyl)oxindoles as PET Ligands for the Serotonin 5‑HT₇ Receptor: Synthesis, Pharmacology, Radiolabeling, and in Vivo Brain Imaging in Pigs

We have investigated several oxindole derivatives in the pursuit of a 5-HT₇ receptor PET ligand. Herein the synthesis, chiral separation, and pharmacological profiling of two possible PET candidates toward a wide selection of CNS-targets are detailed. Subsequent ¹¹C-labeling and in vivo evaluation in Danish landrace pigs showed that both ligands displayed high brain uptake. However, neither of the radioligands could be displaced by the 5-HT₇ receptor selective inverse agonist SB-269970