Potential Safety Hazards Associated with Using Acetonitrile and a

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Potential Safety Hazards Associated with Using Acetonitrile and a Strong Aqueous Base Zhe Wang, Steven M Richter, Michael Rozema, Adam Schellinger, Kimberly Smith, and José G Napolitano Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00158 • Publication Date (Web): 30 Aug 2017 Downloaded from http://pubs.acs.org on August 30, 2017

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Organic Process Research & Development

Potential Safety Hazards Associated with Using Acetonitrile and a Strong Aqueous Base Zhe Wang*, Steven M. Richter, Michael J. Rozema, Adam Schellinger, Kimberly Smith and José G. Napolitano † Process Research and Development, †Discovery Chemistry and Technology, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064 *email: [email protected]

ACS Paragon Plus Environment


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Graph for Use in the Table of Contents


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ABSTRACT Acetonitrile, a common solvent in organic synthesis, can be hydrolyzed in the presence of strong aqueous base, such as NaOH or KOH, which can propagate into a runaway reaction. For a process recently reviewed in our laboratory, a possible loss of cooling incident during the desired reaction was found to have the potential to self-heat to the onset temperature of this hydrolysis reaction. The base-catalyzed acetonitrile hydrolysis was determined to potentially escalate into a runaway reaction, where it could lead to secondary exothermic runaway reactions of the reaction mixture. The use of acetonitrile was preferred for the initial cyclization step. Thus, adequate removal of acetonitrile prior to the following step avoided the process safety hazard posed by the hydrolysis of the acetonitrile solvent. The findings presented in this work serve as an alert to chemists and engineers for the potential safety hazards when scaling up a process in which the solvent becomes a reactant. Keywords: hydrolysis of acetonitrile, process safety, thermal stability, runaway reaction INTRODUCTION Acetonitrile is widely used as a solvent in organic synthesis because it affords high solubility of many organic compounds, miscibility with water and many organic solvents, and modest relative toxicity. Acetonitrile can also be used as a reagent and be catalyzed by strong base or strong acid to undergo hydrolysis to form an amide, and then be further hydrolyzed to a carboxylic acid.1,2 In fact, hydrolysis of nitriles is commonly used to synthesize carboxylic acids. The yield of amide formation may be reduced due to formation of carboxylic acids3,4 as the hydrolysis of amides is faster than the hydrolysis of nitriles under basic conditions.5 Under certain conditions, deprotonation of acetonitrile affords the nitrile-stabilized anion,6 which can



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add to other nitrile molecules to produce dimers or trimers.7 To suppress the hydrolysis, which is competitive with trimer formation, all reactants needed to be dried with molecular sieves prior to heating.8 Acetonitrile under very high pressure and in the presence of a weak base can form trimers.9,10 Neat nitriles have also been trimerized using potassium tert-butoxide as catalyst in a focused microwave reactor.11 To safely scale up a pharmaceutical manufacturing process, a process safety evaluation must be performed. This includes evaluating heats of reaction and the thermal stability of process samples, identifying the process hazards, and defining safe operating conditions. The heat of reaction can be used to determine the adiabatic temperature rise (ATR) of a reaction, while the thermal stability of samples can be used to determine the onset temperatures of exothermic events and their severities. The process temperature (Tp), the maximum temperature rise of the synthesis reaction (MTSR = Tp+ATR), the boiling point of solvent (Tb), and the temperature at which the reaction will reach a maximum self-heating rate under adiabatic conditions in 24 hours (TD24), are used to determine the Criticality Index, introduced by Stoessel12 and shown in Figure 1. This is used to characterize the process hazards into Classes 1 (least critical) to 5 (most critical). The processes in Classes 1 to 3 do not have the thermal potential to reach the decomposition, and the processes in Classes 4 and 5 can potentially self-heat to the onset temperature of decomposition.


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Figure 1. Criticality Classification of Chemical Processes

Tb Tb MTSR

MTSR

TD24 Temperature

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Tb Tb

MTSR

MTSR

MTSR

Tb

Tp

1

2

3 Criticality Class

4

5

In the course of a process safety evaluation for a large-scale cyclization reaction, we identified process risks and subsequent mitigation methods because the desired reaction has sufficient energy to self-heat to the onset temperature of an exothermic runaway reaction associated with acetonitrile and aqueous sodium hydroxide solution. RESULTS and DISCUSSION A pharmaceutical intermediate is formed via the cyclization reaction as shown in Scheme 1. After the completion of cyclization at 55°C using acetonitrile as solvent, the reaction mixture was cooled to ambient temperature. Aqueous sodium hydroxide was added to quench (hydrolyze and neutralize) the trifluoroacetic anhydride (TFAA) and to remove a protective group.



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Scheme 1.

A process safety evaluation was performed to determine if the process could be run safely at the pilot scale. The heat of reaction was obtained using heat flow calorimetry in an Omnical SuperCRC (Chemical Reactivity Calorimeter). The thermal stability of samples was measured by calorimetric methods, such as DSC (Differential Screening Calorimeter), ARC (Accelerating Rate Calorimeter) or VSP2 (Vent Sizing Package 2). DSC was used to quickly screen thermal stabilities of many samples. The ARC has a much higher detection sensitivity, which provides a more accurate onset temperature of exothermic events for key samples from DSC screening. The VSP2, with low thermal inertial, provides the best prediction of a runaway reaction scenario in a larger reactor. Thermal stability screening was performed in the DSC with results summarized in Table 1. Heats of reaction measured with the Omnical SuperCRC are shown in Figure 2, Figure 3, and Table 2. With a 27°C ATR for the cyclization, if cooling is lost, the reaction mixture could selfheat to the MTSR of 82°C. Since the MTSR is lower than the onset temperature of the first exothermic event, and the low energy of the observed event, no thermal stability related safety concerns for the cyclization reaction were identified for this point of the process.


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Table 1. DSC testing results Sample

+84 (endo) -416 -23 -20 -403 -199

Temperature range of thermal event (°C) 142-170 260-324 114-171 175-203 56-209 265-350

-18

166-253

ΔH (J/g)

Starting material Post cyclization Reaction Mixture Post quench and deprotection reaction mixture Product

Figure 2. Cyclization at 55°C Omnical SuperCRC results 59

400 Heat Flow (mW)

58

300

57

200 Add TFAA

56

Add pyridine

o

Temperature ( C)

Temperature (C)

100

55

Heat Flow (mW)

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0

54

-100 50

100

150

200 250 Time (min)

300


350

400


Figure 3. TFAA quench and deprotection at ambient temperature Omnical SuperCRC results 27

3000 Heat Flow (mW)

2500

25

2000

24

1500

23

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22

500

21

0

o

Temperature ( C)

Temperature (C)

26

20

Add NaOH Aq Solution 20

40

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-500 60 Time (min)

80

100

Table 2. Heat of reaction measurement and Criticality analysis results

Heat of reaction (kJ/mol) Reaction temperature (°C) Boiling point of solvent, acetonitrile (°C) ATR (°C) MTSR (°C) Tonset of highly exothermic event in reaction mix (°C) Criticality Index

Cyclization Reaction -255 55 81 27 82 N/A

Quench and De-protection -1103 23 81 66 89 56

1

5

Testing of the reaction mixture after the quench and de-protection with sodium hydroxide included some more concerning results. Two exothermic events were detected in the DSC, including one at 56°C and one near 265°C, each with significant exothermicity. Since the onset temperature of the first exothermic event was near the reaction temperature, the ARC was used to determine a more accurate onset temperature. As shown in Figure 4 and Figure 5, an exothermic event was detected near 40°C and a second exothermic event detected near 210°C


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with temperature rises of 89°C and 146°C, after correcting for thermal inertia. This is in reasonable agreement with the DSC screening. The sodium hydroxide quench and deprotection has an ATR of 66°C, and a MTSR of 89 °C, which is above Tonset, Tb and TD24. This means that the reaction has the thermal potential to self-heat to the onset temperature of the exothermic event without the benefit of evaporative cooling. The NaOH quench and the deprotection reaction fall into Criticality Class 5 in the Stoessel Criticality Index. This is undesired, as there are no inherent safety measures available to mitigate the safety concerns for a Class 5 process. Figure 4. Post quenching TFAA reaction mixture ARC Test Temperature History 350 300 Temperature (°C)

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250 200 150 100 50 0 0

500

1000 1500 Time (min)


2000

2500


Figure 5. Post quenching TFAA reaction mixture ARC Test Self-Heating Rates 1 Self-Heat Rate (°C/min)

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0.1

0.01 0

50

100 150 200 Temperature (°C)

250

300

To examine the severity of the runaway reaction in the event of loss of cooling the quench was performed with a closed cell VSP2 test. The VSP2 has low thermal inertia to simulate runaway behavior in a larger reactor. The test was performed in adiabatic mode, i.e. instead of performing heat-wait-search steps to look for exothermic events, the sample was not heated up with the test heater and the temperature of the test cell environment is controlled by a guard heater to maintain adiabatic conditions. Upon NaOH solution addition (21 equivalents), heat generation quickly increased temperature of the reaction mixture to 70 °C from 30 oC. At this temperature, the self-heating rate never fell below 0.5 °C/min. The exothermic event propagated into a runaway reaction within twenty minutes with observed peak self-heat and pressure rise rates (for the half-full test cell) exceeding 90 °C/min and 200 psi/min. After reaching 175 °C, the self-heat rate decreased and then accelerated into two additional consecutive exothermic events, possibly due to


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decomposition of the reaction mixture. When the temperature reached ~285 °C, the test cell ruptured due to the suspected loss of pressure equalization resulting from a plugged test cell pressure transducer line. Details for the VSP2 test are provided in the Experimental Section. VSP2 testing results are shown in Figure 6 and Figure 7. This test confirms that without cooling, the heat of reaction from quenching TFAA could increase the temperature above the onset temperature of an exothermic event, causing a runaway reaction that eventually escalates into secondary exothermic events at higher temperatures, as suggested by the ARC testing performed with higher thermal inertia. Figure 6. Fresh quenching TFAA reaction mixture VSP2 Test Temperature-Pressure History 500 Temperature (C)

P transducer line block

250

o

Temperature ( C)

Pressure (psig) 200 150

Test cell rupture

300

400 300 200

Secondary exothermic events

Add 50% NaOH 100

100 50

0 Initiation of primary exothermic event

0 0

10

20

30

40 50 Time (min)

-100 60


70

80

Pressure (psig)

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Figure 7. Fresh quenching TFAA reaction mixture VSP2 Test self-heat and pressure rise rates

dT/dt (C/min) 100

100

dT/dt (ºC/min)

dP/dt (psi/min)

10

10

1

1

0.1

20

40

Initiation of primary exothermic event 60 80 100 Temperature (ºC)

dP/dt (psi/min)

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Secondary exothermic events 300

0.1

To identify the cause of the exothermic event, several DSC tests were conducted using combinations of materials used in the process. As summarized in Table 3 and shown in Figure 8, the DSC detected an exothermic event near 56 °C on the post quench reaction mixture. After testing combinations of the reaction mixture components, it was observed that exothermic events were only detected near this temperature when acetonitrile and NaOH aqueous solution are present. It was hypothesized that hydrolysis or polymerization of acetonitrile in the presence of NaOH could be the source of the exothermic event. To explore the cause of the exotherm, a sample was prepared by subjecting the acetonitrile and NaOH aqueous solution in a pressure test cell to 100 °C for two hours to analyze the composition of the exothermic reaction product. Ammonia gas was immediately identified to be present in the post-test gas space. Acetic acid was found to be present in the post-test mixture via 1H NMR analysis. Analysis by LC-MS (positive mode electrospray ionization) also confirmed the presence of acetamide in addition to acetic acid. There was no evidence of dimers or trimers of acetonitrile via LC-MS analysis. All of the LC-MS signals in the positive and negative mode ionization in the sample are accounted for by the signals observed from acetamide, sodium acetate and acetic acid. Thus, it was


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confirmed that acetonitrile was hydrolyzed in the presence of water and strong base, NaOH, to form ammonia, acetamide and acetic acid (then reacts with NaOH to form sodium acetate) as shown in Scheme 2. Scheme 2. Hydrolysis of Acetonitrile

Table 3. DSC screening results of reaction mixture and simulated reaction mixtures Sample

Quench TFAA & deprotection reaction mixture Acetonitrile/50% NaOH/Pyridine Acetonitrile/Pyridine/TFAA Pyridine/TFAA/THF/water/NaOH Pyridine/TFAA/Acetonitrile/NaOH/water Acetonitrile/NaOH/water/TFAA Acetonitrile/NaOH/water


Detection temperature of exotherm (°C) 56 43 122 123 52 58 65


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Figure 8. DSC results of quenched reaction mixture and simulated reaction mixtures

Although base-catalyzed hydrolysis of nitriles is well-known to form amides or carboxylic acids,13 the low onset temperature and amount of heat produced was unexpected. A literature search identified a patented process for removing water and HCN from acetonitrile via extraction with concentrated caustic aqueous solution and with preferred temperatures of approximately ambient but can vary up to 82.5 °C14. Lower temperatures are preferred to minimize hydrolysis of the nitrile which can occur at elevated temperatures, although stability issues were not discussed. Diluted aqueous potassium hydroxide (1 mL of 1% solution per liter) has been used in distillation to purify acetonitrile without reported safety issues.15 To experimentally evaluate how severe the runaway acetonitrile hydrolysis could be under adiabatic conditions a mixture of acetonitrile, water and sodium hydroxide with mole ratio similar to that used in the TFAA quenching and deprotection reaction was also tested with VSP2. An exothermic event was detected at 70 °C, which propagated into a runaway reaction with peak


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self-heat rate and pressure rise rate exceeding 2000°C /min and 5000 psi/min. The exothermic runaway of the acetonitrile, water and sodium hydroxide mixture was more severe than the actual reaction mixture, which is likely due to the lack of reactants, which can act as a heat sink. VSP2 testing results are shown in Figure 9 and Figure 10. Post test mixture analyzed by LC-MS also confirmed the presence of acetamide and acetic acid, products of hydrolysis of acetonitrile and no evidence of dimers or trimers was observed, even after exposure to higher temperature and pressure in this test. Figure 9. Acetonitrile/NaOH/water VSP2 Test Temperature-Pressure History 300

1200 Temperature (C)

250

1000

Cool down

o

Temperature ( C)

Pressure (psia) 68.2g gsample samplewith withsimilar mole ratio: 68.2 mole ratio O 1/0.32/0.72 asACN/NaOH/H in the reaction mixture 2 ACN/NaOH/H O 1/0.32/0.72

200

2

150

800 600

100

400

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Pressure (psig)

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Figure 10. Acetonitrile/NaOH/water VSP2 Test self-heat and pressure rise rates

dT/dt (C/min)

dT/dt (ºC/min)

1000

100

1000

dP/dt (psi/min) 68.2 g sample with similar mole ratio as in the reaction mixture ACN/NaOH/H O 1/0.32/0.72

100

2

10

10

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1

0.1

20

40

60 80 100 Temperature (ºC)

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0.1

Surprisingly, in our review of existing literature, the process hazard potential of this simple combination of commonly used chemicals was not readily available. Although the process may be performed without incident if NaOH solution is added slowly and if sufficient cooling is provided, there are potentially devastating consequences of this runaway reaction upon loss of cooling. Identification of a remedy and development of an inherently safe, robust process was explored before the process could be scaled up in the pilot plant or transferred to a third party manufacturer. A study was performed to investigate if water and sodium hydroxide concentration could be used to reduce the consequences of a runaway reaction. NaOH and water equivalents were varied to observe the effect on the onset temperature. As shown in Table 4, at sodium hydroxide concentrations above 0.1 equivalents, exothermic events were detected in the temperature ranges from 57 to 74 °C. After reducing the


dP/dt (psi/min)

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sodium hydroxide concentration to 0.025 equivalents, the only exothermic event observed was in the sample with 2 equivalents of water, although the detection temperature was much higher, at 157 °C. The plots of DSC results can be found in supplemental material. Table 4. DSC results for acetonitrile, water and NaOH mixtures Entry 1 2 3 4 5 6 7 8 9

Mole ratio Acetonitrile Water NaOH 1 0.5 0.025 1 0.5 0.1 1 0.5 0.3 1 1 0.025 1 1 0.1 1 1 0.3 1 2 0.025 1 2 0.1 1 2 0.3

Tonset (°C) N/D 67 74 N/D 80 57 157 71 65

In the cyclization reaction, approximately 20 equivalents of NaOH with respect to starting material (or about 0.33 equivalents with respect to acetonitrile) is used. Approximately 8 equivalents of NaOH are required to quench TFAA and the rest is needed for the deprotection reaction. The test results suggest that NaOH concentration could be used to reduce the hydrolysis rate of acetonitrile, but only at concentrations well below level required to perform the desired chemical transformation. Since many bases, strong or weak, may be used with acetonitrile in the organic synthesis, the effects of strength of bases on the initiation temperature of acetonitrile hydrolysis were briefly explored with DSC to determine if a weaker base could prevent the runaway reaction. The DSC findings are summarized in Table 5. As shown in Figure 11, when combined with strong bases, such as potassium hydroxide and lithium hydroxide, exothermic events were detected between 60-72 °C, similar to that observed with sodium hydroxide. Additional testing



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showed that the onset temperature of the hydrolysis increased as the strength of the base decreased. In each case that an exothermic event was observed, mixtures were prepared and held at elevated temperatures within the observed exothermic event. Acetamide and acetic acid were observed in NMR analysis of each of the resulting samples. With a pKa of 9.3 or below, heat generation due to hydrolysis of acetonitrile was not observed. One exception was for the organic base DBU (pKa 13.9), in which heat generation due to hydrolysis was not observed. With weaker bases the deprotection reaction may not reach completion. Figure 11. DSC results of Acetonitrile and different bases and salts


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Table 5. DSC results for acetonitrile in water and selected bases and salts Bases*

NaOH KOH LiOH K3PO4 Na2CO3 NH3 NaHCO3 KH2PO4 DBU

pKa16,17 of conjugate acid in water

Detection temperature of exotherm (°C)

Water equiv**

Base equiv**

>14 >14 >14 12.4 10.3 9.3 6.4 6.9 13.5

65 72 60 112 137 N/D N/D N/D N/D

6.9 3.6 5.5 5.9 5.3 4.0 5.7 6.0 2.1

0.3 0.1 0.7 0.2 0.2 4.2 0.1 0.1 0.6

* In acetonitrile/water solution **Calculated with respect to acetonitrile.

The option of removing acetonitrile was also explored. The cyclization reaction performed in THF and 2-methyl THF, but was slow and resulted in unacceptably low yields and additional impurities. To achieve a maximum yield in the cyclization reaction, it was decided to conduct the cyclization in acetonitrile. After the completion of the cyclization, a solvent exchange to 2methyl THF was performed to mitigate the process safety risk during the quench of TFAA and deprotection. The reaction performed this way produced quality product with comparable yield. DSC testing of the post TFAA quenching and deprotection reaction mixtures using 2-methyl THF as solvent did not detect any exothermic event until ~260 °C. The DSC test of the cyclization reaction distillation residue during the solvent switch only detected minor exothermic events near 155 °C and 251 °C. These DSC results as well as the DSC results of post cyclization reaction mixture are shown in Figure 12.



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Figure 12. DSC results of process samples from final process

CONCLUSION Following the cyclization reaction in acetonitrile, the quench of TFAA and deprotection with aqueous sodium hydroxide solution was found to be unsafe to scale up. In the event of a loss of cooling, the heat of reaction from the desired reaction has the thermal potential to escalate into an exothermic runaway reaction. Since the cyclization was not found to be effective in alternative solvents, it was performed in acetonitrile. A robust and safe alternative process was identified by switching the solvents from acetonitrile to 2-methyl THF to perform the quench and deprotection reaction. By eliminating a potential runaway reaction, the Stoessel Criticality risk level was reduced from Class 5, with the potential to reach and no inherent protection against a runaway reaction, to a


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Class 1, where the process no longer has a way to reach a thermal hazard on its own. The modified process has been successfully scaled up in pilot plant. This work shows an example where the combination of acetonitrile with a strong base could pose significant safety concerns due to runaway reaction caused by acetonitrile hydrolysis. Even though acetonitrile hydrolysis is known to happen in the presence of water and strong base, hydrolysis reactions are often mildly exothermic.

Therefore, it was unexpected that the

hydrolysis reaction posed a safety risk at easily achievable temperatures in this process. The energy from the desired reaction is sufficient to self-heat the reaction mass past the onset temperature of the hydrolysis reaction, and then the secondary runaway reactions of the mixture.

propagate into a runaway reaction and trigger By replacing acetonitrile before the NaOH

quench, the process risk due to potential runaway reaction caused by hydrolysis of acetonitrile has been eliminated. Although not tested as a part of this work, similar safety concerns could exist with mixtures of acetonitrile and acids.18 The findings presented in this work may serve as an alert to chemists and engineers for the potential safety hazards when the solvent becomes a reactant, as acetonitrile does in the presence of the strong base. EXPERIMENTAL SECTION: Equipment used: Differential scanning calorimetry (DSC) was performed using a Mettler-Toledo DSC821e or DSC823e using sealed glass ampoules with a capacity of approximately 50 µL. Accelerating rate calorimetry (ARC) was performed using a Netzsch ARC 254 and titanium test cells. VSP2 testing was performed using Fauske & Associates Vent Sizing Package 2. Heat of reaction testing was performed using an Omnical SuperCRC isothermal



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calorimeter. Liquid chromatography mass spectrometry (LCMS) was performed using an Agilent 1260 HPLC instrument with an Agilent 6130 single quad mass spectrometer. General Procedure for DSC testing: Samples were first loaded into and sealed in glass ampoules and ramped in the DSC furnace from 0°C to 250 - 350°C at 1 - 3°C/minute. General Procedure for Omnical Testing: Two 15 mL glass test cells were used per test, one for the sample and the other for the reference. Mixing was provided by a magnetic stir bar. General Procedure for ARC testing: The sample was loaded into a Ti pressure bomb, which was then inserted into the calorimeter. Temperature and pressure of the test were recorded. The sample was heated in heat-wait-search steps of 10°C, starting at 30°C. When self-heating was detected, the calorimeter maintained the airspace around the bomb at the same temperature as the sample and tracked the exotherm to 300°C or until reaching a pressure of 40 - 70 bar. General Procedure for LCMS testing: Samples were prepared by weighing about 55 mg of material and diluting with 1 mL of water containing 0.1% (v/v) formic acid. Water containing 0.1% (v/v) formic acid was used as the aqueous mobile phase, and acetonitrile was used as the organic mobile phase. The LCMS conditions can be found in the table below. A XBridge C18 HPLC column from Waters (150 x 4.6 mm, 3.5 µm particle size) was used. Table 6. HPLC Instrument Parameters HPLC Parameters Flow Rate: 1.0 mL/min Injection Volume: 3.0 µL Column Temperature: 30°C UV Wavelength: 210 nm UV Bandwidth: 4 nm

Time (min) 0.0 15.0 20.0 20.1 25.0

HPLC Gradient Aqueous Mobile Organic Mobile Phase Percent Phase Percent 90 10 0 100 0 100 90 10 90 10


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Table 7. Mass Spectrometer Instrument Parameters Mass Spectrometer Parameters Ionization Source: Electrospray Drying Gas Temperature: 350°C Drying Gas Flow Rate: 12 l/min Capillary Voltage: 3000 V Nebulizer Pressure: 50 psig Fragmentor Voltage: 70 V Gain: 1 Positive and Negative Scan Mode Used

General Procedure for VSP2 Testing: A closed cylindrical stainless steel test cell (~120 mL) was placed in a 4 L containment vessel. The test cell was enclosed by a test heater, a layer of insulation, and a guard heater which is in turn enclosed by thermal insulation. Mixing was provided by a magnetic stir bar. The sample temperature and pressure as well as the containment pressure were recorded. The VSP2 test cell with charges shown in the following tables was loaded into a VSP2 vessel and heated in heat-wait-search steps. When self-heating was detected, the calorimeter maintains adiabatic conditions by offsetting heat losses through the guard heater and tracks the exotherm to the temperature or pressure limits defined for the test. As test cell pressure increased, nitrogen was charged into the containment vessel to maintain the specified test cell and containment pressure differential. Omnical test charges: Charges for cyclization, hydrolyzing TFAA and deprotection during the Omnical test are shown in Table 8. The cyclization reaction was performed at 55°C. After the cyclization reaction reached completion, a new test was started at 23°C then NaOH solution was added. After the



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reaction reached completion, 5.13 g of the reaction mixture was used to test the thermal stability in the ARC. Table 8. Omnical test charges for cyclization, hydrolyzing TFAA and deprotection using acetonitrile as solvent (7.64 g total) Material Starting material Pyridine TFAA Acetonitrile NaOH Water

Equivalents 1.00 4.82 4.79 60.44 22.43 49.84

Reaction for hydrolyzing TFAA and deprotection closed cell VSP2 test charges: Charges for the VSP2 test to simulate cooling failure during the initially proposed process are shown in Table 9. The reaction mixture, without 50% NaOH, was first subject to 55°C heating for several hours until the cyclization reaction reached completion. The reaction mixture was then cooled down and loaded into the VSP2 test cell. The VSP2 test was started in adiabatic tracking mode (without heating up sample). The exothermic events were detected upon the addition of 50 wt% NaOH, which led to runaway reaction, as shown in Figure 7. Table 9. VSP2 test charges for hydrolyzing TFAA and deprotection (66.32 g total) Material Starting material Pyridine TFAA Acetonitrile NaOH Water

Equivalents 1.00 3.32 4.18 55.28 20.91 46.46

ASSOCIATED CONTENT Supporting Information


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Graphic illustration of DSC results for mixtures of acetonitrile, water and NaOH at different ratios, reaction mixture and simulated reaction mixtures, and mixtures of acetonitrile with different bases and salts. ACKNOWLEDGEMENTS The design, conduct study, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, writing, reviewing, and approving of the publication. All authors are employees of AbbVie. REFERENCE 1

Jerry March, Advanced Organic Chemistry Reactions, Mechanisms, and Structure, 6-5, 2nd Ed. 1977, McGraw–Hill, Inc. 2 Parris, C. L.; Christenson, R. M. JOC 1960, 25,331, N–Alkylation of Nitriles with Benzyl Alcohol, Related Alcohols, and Glycols1, 10.1021/jo01073a006 3 Ghaffar, T., Parkins, A. W., The catalytic hydration of nitriles to amides using a homogeneous platinum phosphinito catalyst, J. Mol. Catal. A: Chem. 160, 2000, 249. 4 Parkings A. W., Catalytic hydration of nitriles to amides, Platinum Met. Rev., 60, 1996, 169. 5 Chin, J. Developing artificial hydrolytic metalloenzymes by a unified mechanistic approach, Acc. Chem. Res., 1991, 24, 145, 10.1021/ar00005a004 6 Gornowicz, G. A.; West, R. JACS 1971, 93 1714, Polylithium compounds. IV. Polylithiation of nitriles and the preparations of trisilylynamines, 10.1021/ja00736a025 7

Kruger C. JOM (The Member Journal of The Minerals, Metals & Materials Society) 1967, 9, 125. 8 Smyrl, N. R.; Smithwick, R. W. J. Heterocycl. Chem. 1982, 19(3), 493, Hydroxide–catalyzed synthesis of heterocyclic aromatic amine derivatives from nitriles, http://dx.doi.org/10.1002/jhet.5570190309 9 Bengelsdorf, I. S. J. Org. Chem. 1963, 28(5), 1369, High Pressure–High Temperature Reactions. II. The Reactions of Aliphatic Nitriles and Amides, http://dx.doi.org/10.1021/jo01040a053 10

Cairns, T. L.; Larchar, A. W.; McKusick, B. C. J. Am. Chem. Soc. 1952, 74(22), 5633, The Trimerization of Nitriles at High Pressures, http://dx.doi.org/10.1021/ja01142a028 11

Baxendale, I. R.; Ley, S. V. J. Comb. Chem. 2005, 7(3), 483, Formation of 4– Aminopyrimidines via the Trimerization of Nitriles Using Focused Microwave Heating, http://dx.doi.org/10.1021/cc049826d

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Stoessel, F. Thermal Safety of Chemical Processes-Risk Assessment and Process Design. Basel, CH, WILEY-VCH Verlag GmbH & Co. KGaA, 2008. 13 Carey, F. Organic Chemistry, McGraw-Hill, Inc., 2nd Ed., 1982



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Smiley, R. A. US Patent 4287134, 1981, Purification of Acetonitrile by Caustic Extraction Coetzee, J. F. Pure Appl. Chem. 1966, 13(3), 427, Purification of acetonitrile and tests for impurities, http://dx.doi.org/10.1351/pac196613030427

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Kaupmees, K., Trummal, A., Leito, I., Basicities of Strong Bases in Water: A Computational Study, Croat. Chem. Acta, 2014, 87, 385-395. 17 Carey, F. Organic Chemistry, 2nd Ed., 1982, McGraw-Hill, Inc. 18 Bretherick, L. Handbook of Reactive Chemical Hazards. 6th ed. Boston, MA: ButterworthHeinemann Ltd., 1999, p. 281


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Potential Safety Hazards Associated with Using Acetonitrile and a

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