Thermal Stability of 2-Butynoic Acid (Tetrolic Acid)

Article abstract of DOI:10.1021/acs.oprd.9b00106

Work to assess the thermal properties of 2-butynoic acid (a precursor to acalabrutinib) has revealed the potential for thermal runaway on heating; testing using accelerated rate calorimetry (ARC) showed exothermic onset from 135 °C, precluding short-path distillation as a means of purification. Recrystallization was shown to be effective as an alternative technique to purify the compound and avoid the distillation procedure.

Full text of DOI:10.1021/acs.oprd.9b00106

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Communication
Thermal Stability of 2-Butynoic Acid (Tetrolic Acid)
Hannah Ashton, Paul A. Bethel, Sarah-Kate Cantlie, Trevor Churchill,
Katie Cooper, Benjamin Dobson, Michael Golden, and Mark Hoyle
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00106 • Publication Date (Web): 18 Apr 2019
Downloaded from http://pubs.acs.org on April 19, 2019
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Thermal Stability of 2-Butynoic Acid (Tetrolic Acid)
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Authors
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Hannah Ashton, Paul A. Bethel, Sarah-Kate Cantlie, Trevor Churchill, Katie Cooper,
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Benjamin Dobson, Michael Golden*, Mark Hoyle.
† Pharmaceutical Technology and Development, AstraZeneca, Silk Road Business Park,
Macclesfield SK10 2NA, United Kingdom.
Corresponding author
michael.golden@astrazeneca.com
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TOC abstract
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Abstract
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Work to assess the thermal properties of 2-butynoic acid (a precursor to acalabrutinib) has
revealed the potential for thermal runaway on heating; testing using Accelerated Rate
Calorimetry (ARC) showed exothermic onset from 135°C, precluding short path distillation
as a means of purification. Recrystallisation was shown to be effective as an alternative
technique to purify the compound and avoid the distillation procedure.
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Keywords
2-butynoic, tetrolic, acid, thermal, stability
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Introduction
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2-Butynoic acid (Figure 1), was first reported in 1871 by Geuther as part of his work on
ethylacetoacetate derivatives1 and has wide application as a building block in organic
synthesis. It exists as a highly crystalline solid, with a melting point of approximately 78 to
80°C. Several lab scale synthetic methods to produce 2-butynoic acid are reported in the
literature.2,3,4 Predominantly, the use of a base to deprotonate propyne, followed by reaction
with carbon dioxide and quench into aqueous acidic solution, has been used to give high
yields in one synthetic step. Small scale purification by distillation is also reported.4
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Recently, the use of 2-butynoic acid as a precursor in the production of acalabrutinib5 (Figure
1), a BTK inhibitor (approved for use in the treatment of Mantle Cell Lymphoma6), has
required large-scale production and purification techniques to be developed. The purpose of
this study was therefore to assess the suitability of the existing literature methodology for
scale-up; specifically, the use of distillation to purify, which was seen as having the potential
for thermal runaway.
Figure 1 – 2-Butynoic acid and acalabrutinib
N
O
N H
N H2
N
N
N
O
O
(S)
HO
N
2-Butynoic acid
Acalabrutinib
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Results and discussion
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Following reported methodology4 to synthesise 2-butynoic acid, n-butyl lithium was chosen
as the base (to de-protonate propyne prior to reaction with carbon dioxide), with a view to
scaling this process, to provide commercial volumes. On application of this synthesis, only
one significant impurity was observed in the 2-butynoic acid produced, which was identified
as 2 (Figure 2). The formation of this impurity was initially difficult to rationalise; however,
degradation of n-butyl lithium/tetrahydrofuran mixtures is known in the literature7, forming
acetaldehyde (and ethene), specifically at temperatures above -70°C. Acetaldehyde appears to
be the most likely precursor in the formation of 2 and this degradation pathway matched
observations, such that higher temperature during the deprotonation of propyne appeared to
give increased levels of 2.
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Figure 2 – 2-Butynoic acid synthesis, and impurity (2)
CO2 / H+
n-BuLi
THF
O
– C
HO
2-Butynoic acid
(1)
Propyne
O
O H
HO
(2)
Initially, short path distillation, as reported in the literature,4 was used as a means of
purification of early manufacturing batches, which appeared to remove any colouration, and
also efficiently removed the impurity 2, producing highly crystalline, white solid, of excellent
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quality. The 2-butynoic acid is seen to melt at approximately 78-80°C, and, using high
vacuum, the melt can be distilled at temperatures of approximately 120-130°C. However,
subsequent, more thorough investigation into the thermal properties of 2-butynoic acid
revealed the potential for thermal runaway, ruling out this method of purification for future
manufactures.
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Process Safety investigation of thermal stability of 2-butynoic acid
It is not surprising that the heat of decomposition of 2-butynoic acid is significant given the
alkyne functionality is considered a ‘highly energetic functional group’ (HEFG) and also has
potential to confer explosive properties in a molecule. This energy output was clearly evident
in the initial thermal stability screening of the material (Figure 3).
Figure 3 : Differential Scanning Calorimeter Trace : 2-butynoic acid (40 µL HP Gold cell,
5K/min ramp rate)
Yoshida correlations8 provide a method of predicting potential explosive properties from the
defined exothermic activity onset temperature in this test (123°C) and the decomposition
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energy noted (-2300 J/g), and this proved positive, i.e. it did indicate potential issues in this
respect. It was considered that the structure would be unlikely to fall in to true classification
as a Class 1 explosive, as defined by the UN Recommendations on the Transport of
Dangerous Goods Model Regulations9, and further screening tests proved this to be the case.
A test correlated to screening tests9 is an in-house test called the High Rate Carius tube, it
essentially measures the rate of pressure rise, this showed an extremely slow rate between
correlated points against known explosives10. Even though considered not to be explosive,
the actual energy involved in the self-reactivity/decomposition of this material would be an
obvious safety issue if it could be accessed under the proposed operating conditions. Given
that relatively high temperature vacuum distillation of the material was under consideration
(120-130°C), the decomposition ’onset’ seen in DSC11,12,13 (which has limited sensitivity with
respect to ‘onset’ detection) gave significant concern for large scale application of short path
distillation. Further, thermal stability testing using increased sensitivity calorimetric
techniques (Setaram C80 and Accelerating Rate Calorimeter (ARC)) and using the data in
application of both Time to Maximum Rate (TMR) and Thomas14 modelling indicated that it
would be unsafe to conduct a vacuum distillation at anything other than a very small scale.
In fact, the ARC showed the potential consequence of initiating thermal decomposition of this
material in any significant amount by the manner in which the cell ruptured very dramatically
at high pressure (Figure 4).
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Figure 4: ARC thermograph of 2-butynoic acid (Hastelloy bomb, 5.11g 2-butynoic acid
H-W-S from 40°C).
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Time to maximum rate (under adiabatic conditions) (TMRad) calculation based on the most
sensitive calorimetric data indicated a time of around 84 minutes (to explosion/rupture),
which is clearly unsafe with respect to taking any realistic emergency action to avoid over-
pressurisation and probable rupture of the reactor. Usually a maximum temperature (TD24
)
where TMRad = 24 hours is a minimum safety requirement. TD24, here would be a maximum
exposure temperature of 74°C, and usually an additional safety margin is applied to this
(typically allowing exposure to a maximum of TD24 -10K (or more depending on viscosity of
material)). Given the likely boiling point of the material, even under vacuum distillation, it
was evident that this would not be a safe large-scale batch operation.
Purification, drying and storage
Seeking an alternative to distillation (as a means of purification), it was demonstrated that
recrystallisation of the crude material (by dissolving in methyl tert-butyl ether and swapping
into heptane to crystallise), efficiently removed the amount of impurity 2 to trace levels,
producing suitable quality material without the requirement to distil. Additionally, it was
observed that the 2-butynoic acid sublimes when drying in the vacuum oven at temperatures
above ambient. Production on pilot scale was performed using a flow of nitrogen (or by tray
drying under vacuum) at ambient temperature to dry the product from the crystallisation
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solvent, heptane. The 2-butynoic acid is then stored, as a crystalline solid, in sealed bags at 2-
8°C to prevent any losses on storage.
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Scale up of the literature methodology4 to produce commercial volumes of 2-butynoic acid
was problematic due to the thermal instability of the product, which prevented the use of short
path distillation as a means to purify the product. Specifically, control of the formation of an
impurity (thought to be formed due to degradation of n-butyl lithium and tetrahydrofuran) was
necessary, and a recrystallisation procedure was developed to facilitate this, which avoided
the need for distillative purification.
Experimental Section
2-Butynoic acid (9.33 kg, 1.0 mol eq) was dissolved in methyl tert-butyl ether (18.7 L, 2.0 rel
vols) and transferred through an in-line filter to a second vessel, rinsing the dissolving vessel
and filter with a methyl tert-butyl ether (4.7 L, 0.5 rel vol) line wash. Heptane (42 L, 4.5 rel
vol) was added to the solution and the mixture concentrated under vacuum (200 mbar) to a
fixed volume (28 L, 3.0 rel vols). Added heptane (28 L, 3.0 rel vol) and concentrated under
vacuum (200 mbar) to a fixed volume (28 L, 3.0 rel vols). The batch was cooled to 5°C over
1 hour and then filtered, washing the filter cake with heptane (18.7 L, 2.0 rel vols). Dried at
ambient temperature under vacuum overnight to yield a white crystalline solid (9.11 kg,
1
97.6%). H NMR (500 MHz, CDCl3) δ 2.03 (s, 3H), δ 11.06 (s, br, 1H). 13C NMR (126
MHz, CDCl3) δ 3.5, 71.6, 88.3, 158.1. HRMS (ESI) for C4H3O2 (M-H-); calcd, 83.0139;
found, 83.0148.
Differential Scanning Calorimetry (DSC)
Model: Mettler-Toledo DSC 3+
Pan Type: Gold High Pressure 3-piece 40µL pan
Ramp Rate: 5K/min
Range: 0-500oC
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Evaluation: Mettler-Toledeo STARe Excellence Software
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Accelerating Rate Calorimetry (ARC)
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Model: Thermal Hazard Technology ESARC
Bomb Type: Hastelloy – HCMBQ
Mode: Heat-Wait-Seek
Start temp: 40oC
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End Temp: 350oC
Interval: 5K
Wait: 15 min
Temp Rate Sensitivity: 0.02oC/min
Safety Pressure: 200 bar
References
1. Geuther, A.; J. Chem. Soc. 1871 (24), p812–837.
2. Smith, W. U.S. Patent 3,752,848A, 1973.
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temperature”. DSC software will also report an “onset temperature” but this reported
value is an extrapolated value taken from the peak exotherm rate and extrapolated back to
the baseline. The left-limit onset temperature is a more conservative value and can be
selected by the individual performing the DSC experiment (with standard normalisation of
output to sample size (W/g), setting of the viewing (Y) axis over 4 W to reduce any
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equipment).
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