Thermal Stability of 2-Butynoic Acid (Tetrolic Acid)

Ashton, Hannah; Bethel, Paul A.; Cantlie, Sarah-Kate; Churchill, Trevor; Cooper, Katie; Dobson, Benjamin C.; Golden, Michael; Hoyle, Mark

doi:10.1021/acs.oprd.9b00106

Cited by 2 publications

(4 citation statements)

References 7 publications

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“…Early batches of the key intermediate, 2-butynoic acid (tetrolic acid), required purification by distillation, which yielded excellent quality material. However, thermal analysis of the distillation procedure revealed a thermal runaway (onset at approximately 135 °C), which precluded the use of this purification technique . A recrystallization procedure was developed to ensure that suitable quality material could be isolated.…”

Section: Resultsmentioning

confidence: 99%

“…A recrystallization procedure was developed to ensure that suitable quality material could be isolated. This work is detailed in a separate publication …”

Section: Resultsmentioning

confidence: 99%

“…The use of two pressure filters and multiple manual discharges of the product (as a wet paste) was considered operable only up to a 50 kg scale and only with a significant time penalty. Additionally, the production of 2-butynoic acid (tetrolic acid) required purification by distillation, which was found to be thermally hazardous, and could not be used for onward production of this key material. The acylation to produce 1 was also problematic, and multiple batch failures had occurred, more worryingly, through a variety of different failure modes; impurities due to both under- and over-reaction were problematic, and an N -acetyl impurity was observed at variable levels, the source of which and its mechanism of formation were unknown.…”

Section: Introductionmentioning

confidence: 99%

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Development of Commercial Manufacturing Processes for Acalabrutinib

Bethel

Chan

Cooper

et al. 2022

Org. Process Res. Dev.

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The development of processes to produce the Bruton tyrosine kinase inhibitor, acalabrutinib 1, has resulted in improvements to the yield, cycle time, and operability, to realize a robust commercial manufacturing process. A highly accelerated clinical program meant that numerous key process challenges had to be resolved in a short timeframe. Issues are discussed, such as the uncontrolled epimerization of a chiral center and the control of the acalabrutinib 1 crystallization step, which was prone to oiling. Specifically, work to understand the complex polymorph landscape of a key intermediate (to facilitate resolution of a filtration issue) is described.

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Section: Resultsmentioning

confidence: 99%

“…A recrystallization procedure was developed to ensure that suitable quality material could be isolated. This work is detailed in a separate publication …”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development of Commercial Manufacturing Processes for Acalabrutinib

Bethel

Chan

Cooper

et al. 2022

Org. Process Res. Dev.

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“…But-2-ynoic acid (entry 4) is an excellent example of how the O.R.E.O.S. tool can be used to identify high-hazard compounds early in development and serves as a reminder that alkynes can undergo highly exothermic decomposition reactions . The material possesses a low thermal onset and a known ExFG, fails the Rule of 6 calculation, and is classified as Medium by the OB calculation.…”

Section: Applying the Oreos Methodsmentioning

confidence: 99%

Explosive Hazard Identification in Pharmaceutical Process Development: A Novel Screening Method and Workflow for Shipping Potentially Explosive Materials

Sperry

Azuma

Stone

2021

Org. Process Res. Dev.

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When a material is identified as potentially capable of explosive propagation by the Yoshida correlation, process safety scientists have few options for semiquantitatively assessing the hazards associated with the use of that material. Oxygen balance calculations, the Rule of 6, and the United Nations (U.N.) explosive functional group list are commonly employed qualitative/semiquantitative methods to assess explosivity without requiring additional experimental data. In contrast, a full United Nations Transportation of Dangerous Goods testing regimen requires, at a minimum, 2 kg of material for Test Series 1 alone, an excessive amount that is rarely available in early pharmaceutical development. A new assessment, called the O.R.E.O.S. method, has been developed that combines the three traditional methods for screening of explosive properties (Oxygen balance calculations, the Rule of 6, and the Explosive functional group list) with the Onset of decomposition determined by differential scanning calorimetry and the proposed Scale. This new assessment has been applied to known energetic materials that are flagged as potentially capable of explosive propagation by the Yoshida correlation and has been shown to be effective at classifying materials in a scale-dependent manner. The tool is customizable to fit any organization’s internal guidance on handling energetic materials. This assessment should find wide utility in both pharmaceutical development groups and contract research organizations as a means to classify compounds that may require further testing before scale-up or to steer project teams to discover safer alternatives. A brief description of the challenges associated with transporting materials for U.N. Series Testing is also presented with the aim of demystifying the process for obtaining such valuable data.

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Thermal Stability of 2-Butynoic Acid (Tetrolic Acid)

Cited by 2 publications

References 7 publications

Development of Commercial Manufacturing Processes for Acalabrutinib

Development of Commercial Manufacturing Processes for Acalabrutinib

Explosive Hazard Identification in Pharmaceutical Process Development: A Novel Screening Method and Workflow for Shipping Potentially Explosive Materials

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