7 research outputs found
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‑HT<sub>7</sub> Receptor: Synthesis, Pharmacology, Radiolabeling, and in Vivo Brain Imaging in Pigs
We
have investigated several oxindole derivatives in the pursuit
of a 5-HT<sub>7</sub> 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 <sup>11</sup>C-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-HT<sub>7</sub> receptor
selective inverse agonist SB-269970