Continuous Safety Improvements to Avoid Runaway Reactions: The Case of a Chloro-Thiadiazole Intermediate Synthesis toward Timolol

Agosti, Alessandro; Panzeri, Silvia; Gassa, Federico; Magnani, Massimo; Forni, G; Quaroni, Marco; Feliciani, Lazzaro; Bertolini, Giorgio

doi:10.1021/acs.oprd.0c00048

Cited by 3 publications

(4 citation statements)

References 8 publications

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Section: Results and Discussionmentioning

confidence: 99%

“…The adiabatic temperature rise (Δ T ad ) is used to evaluate the severity of a runaway reaction, while the time to maximum rate under adiabatic conditions ( TMR ad ) is used to evaluate the probability of a runaway reaction. On this basis, Stoessel proposed the Stoessel assessment criteria. , By comparison of four temperatures as risk assessment criteria, namely, the process temperature ( T p ), the maximum temperature for technical reasons ( MTT ), the MTSR , and the temperature at which the TMR ad is 24 h ( T D24 ), the criticality of runaway can be determined. The criticality value is used to evaluate the risk of a runaway reaction in order to prevent the occurrence of a cooling failure.…”

Section: Introductionmentioning

confidence: 99%

“…On this basis, Stoessel proposed the Stoessel assessment criteria. 4,5 By comparison of four temperatures as risk assessment criteria, namely, the process temperature (T p ), the maximum temperature for technical reasons (MTT), the MTSR, and the temperature at which the TMR ad is 24 h (T D24 ), the criticality of runaway can be determined. The criticality value is used to evaluate the risk of a runaway reaction in order to prevent the occurrence of a cooling failure.…”

Section: Introductionmentioning

confidence: 99%

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Research on the Risk of Thermal Runaway in the Industrial Process of Styrene Solution Polymerization

Zhao

Zhang²,

et al. 2021

Org. Process Res. Dev.

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Polymerization reactions are exothermic processes that are often accompanied by viscosity changes, and they can pose hazards due to thermal runaway. This paper describes an investigation of the potential for thermal runaway in the industrial process of styrene solution polymerization, in which particular focus was devoted to the effects of the monomer concentration and the solvent. As the monomer concentration increased from 20.0 to 50.0 wt %, the heat of reaction Q r and the adiabatic temperature rise ΔT ad increased in a linear manner from 19.0 ± 0.2 to 58.1 ± 0.6 kJ and 21.7 ± 0.1 to 64.8 ± 0.6 K, respectively, and the maximum temperature attained by the synthesis reaction (MTSR) was also increased from 86.1 ± 0.2 to 101.5 ± 0.2 °C. In addition, the molecular weight distribution of polystyrene was around 1.9, and the distribution was broad. The risk of a potential runaway reaction was evaluated using the Stoessel assessment criteria and Zurich Hazard Analysis. The criticality of runaway polymerization remained constant with increasing concentration, and class 1 risk was observed. However, the severity of a potential runaway reaction was increased from negligible to medium class. It was found that the solvent had an important effect on the risk of thermal runaway during polymerization. The criticality of the high-boiling solvents toluene and cyclohexanone used in this work was class 1, while that of the low-boiling solvent ethyl acetate was class 3. This work provides valuable insight that can help to control thermal risk in the chemical industry.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Research on the Risk of Thermal Runaway in the Industrial Process of Styrene Solution Polymerization

Zhao

Zhang²,

et al. 2021

Org. Process Res. Dev.

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“…These challenges motivated us to back-integrate the synthesis of 1 into our supply plan to ensure timely delivery and acceptable quality attributes were obtained to support sample production. However, oxodiazoles are known as highly energetic compounds, which required rigorous process safety understanding and development of appropriate mitigation strategies to ensure safer production of this material. In addition, transportation options for this material might be limited by its inherent potential explosive properties.…”

Section: Introductionmentioning

confidence: 99%

Safety Guided Process Development and Scale-Up of the Highly Energetic Compound 4-Methyl-1,2,5-oxadiazole-3-carboxylic Acid

Yang,

Lu,

Xia

et al. 2024

Org. Process Res. Dev.

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The synthesis of the highly energetic pharmaceutical intermediate 4-methyl-1,2,5-oxadiazole-3-carboxylic acid via cyclization of (2E,3E)-butane-2,3-dione dioxime followed by selective oxidation of the resulting 3,4-dimethyl-1,2,5-oxadiazole was developed to support the sample production for clinical trials. Rigorous process safety evaluations revealed many potential safety risks associated with the involved highly energetic compounds and the high exothermicity of the oxidation reaction. A continuous flow process was developed for the synthesis of 3,4-dimethyl-1,2,5-oxadiazole to mitigate the potential safety risks associated with the thermal instability of starting material (2E,3E)-butane-2,3-dione dioxime and product 3,4-dimethyl-1,2,5-oxadiazole. A much safer process for the highly exothermic oxidation of 3,4-dimethyl-1,2,5-oxadiazole involving portion-wise addition of potassium permanganate was developed to avoid accumulation of reactive chemicals. The desired product was isolated as N-methyl morpholine 4-methyl-1,2,5-oxadiazole-3-carboxylate to avoid handling of potentially explosive 4-methyl-1,2,5-oxadiazole-3-carboxylic acid in its solid form. The developed process was successfully scaled up to afford a total of 93.52 kg of N-methyl morpholine 4-methyl-1,2,5oxadiazole-3-carboxylate to support the production of a drug substance.

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Safety risk assessment of epoxy acrylate prepared by ring-opening esterification of epoxy resin and acrylic acid

Li,

Zhang,

et al. 2024

J Therm Anal Calorim

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Continuous Safety Improvements to Avoid Runaway Reactions: The Case of a Chloro-Thiadiazole Intermediate Synthesis toward Timolol

Cited by 3 publications

References 8 publications

Research on the Risk of Thermal Runaway in the Industrial Process of Styrene Solution Polymerization

Research on the Risk of Thermal Runaway in the Industrial Process of Styrene Solution Polymerization

Safety Guided Process Development and Scale-Up of the Highly Energetic Compound 4-Methyl-1,2,5-oxadiazole-3-carboxylic Acid

Safety risk assessment of epoxy acrylate prepared by ring-opening esterification of epoxy resin and acrylic acid

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