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Cite This: Org. Process Res. Dev. 2018, 22, 1262−1275

Thermal Stability Assessment of Peptide Coupling Reagents Commonly Used in Pharmaceutical Manufacturing Jeffrey B. Sperry,*,† Christopher J. Minteer,† JingYa Tao,† Rebecca Johnson,‡ Remzi Duzguner,† Michael Hawksworth,‡ Samantha Oke,‡ Paul F. Richardson,∥ Richard Barnhart,† David R. Bill,† Robert A. Giusto,† and John D. Weaver III†

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†

Pfizer Chemical Research andDevelopment, Process Safety Laboratories, 558 Eastern Point Road, Groton, Connecticut 06340, United States ‡ Pfizer Chemical Research and Development, Process SafetyLaboratories, Ramsgate Road, Sandwich CT13 9NJ, United Kingdom ∥ PfizerWorldwide Medicinal Chemistry, 10770Science Center Drive, San Diego, California 92121, United States S Supporting Information *

ABSTRACT: Amide couplings are one of, if not the most common chemical reactions performed in the pharmaceutical industry. Many amide bonds are generated with the help of highly active peptide coupling reagents. These reagents have garnered wide use in the pharmaceutical industry, but many contain high-energy functional groups. As a result, significant time is spent assessing the thermal stability of these reagents before scale-up commences. This paper assesses the thermal stability of 45 common peptide coupling reagents by differential scanning calorimetry and accelerating rate calorimetry. Those compounds which flagged as potentially impact-sensitive or potentially explosive were tested by drop hammer and explosivity screening techniques. The data are presented in an effort to drive the development of these reactions toward the use of one of the more thermally stable reagents. KEYWORDS: thermal stability, peptide coupling reagent, differential scanning calorimetry, explosivity

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INTRODUCTION Peptide coupling, a condensation reaction between a carboxylic acid and an amine, is widely believed to be first reported by Fisher and Fourneau in 1901.1 Although this publication introduced the term “peptide”, the first example of a peptide synthesis was reported by Curtius in 1882 during his doctoral research studies in the Kolbe lab.2 Since the first simple dipeptides were synthesized by Curtius and Fisher over a century ago, peptide synthesis has undergone dramatic development with the advent of peptide coupling reagents.3 The global peptide drug market has been predicted to generate more than $25 billion in 2018 based on a review of the topselling peptide therapeutics in Transparency Market Research.4 The direct condensation of a carboxylic acid and an amine is not practical for the generation of most, if not all, pharmaceutical intermediates due to proton exchange between the two coupling partners. In early drug discovery, extreme conditions such as high temperature5 and microwave irradiation6 can be used for the generation of pharmaceutical analogues, but these techniques have yet to become common in pharmaceutical and fine chemical manufacturing plants due to limitations of scalability. As a result, acid activation by peptide coupling reagents is often required to promote the coupling of the activated acid with an amine. Some of these reagents are derived from high-energy functional group containing molecules such as 1-hydroxybenzotriazole (HOBt), a known explosive material when dry, and 1hydroxyazabenzotriazole (HOAt) (Figure 1).7 The use of these reagents on a large scale often requires a significant amount of safety testing to ensure processes are safe. In this © 2018 American Chemical Society

Figure 1. Structures of HOBt and HOAt.

publication, we assess the thermal stability of common peptide coupling reagents, many of which have already been reported on >1 kg scale8 with the hope that the data contained herein will help drive the development of inherently safer chemical processes.9 A recent publication by Glaxo-Smith-Kline should also be considered when developing amidation processes.10 Differential scanning calorimetry (DSC) is an invaluable tool to process safety scientists.11 With only a few milligrams of sample, DSC data provide thermal onset temperatures and quantitative heats of decomposition. DSC data can also be used to screen for potential impact sensitivity and explosivity based on the Yoshida correlations.12 The Yoshida correlations are mathematical equations used to predict a material’s potential to exhibit impact sensitivity and explosivity as a function of its DSC onset temperature and the energy associated with its exothermic decomposition. The Yoshida correlations are given by eq 1 (for shock sensitivity (SS)) and eq 2 (for explosive propagation (EP)). If a compound’s SS or EP value is ≥0, then the material is classified as potentially Received: June 22, 2018 Published: July 30, 2018 1262

DOI: 10.1021/acs.oprd.8b00193 Org. Process Res. Dev. 2018, 22, 1262−1275

Organic Process Research & Development

Article

Figure 2. Yoshida and Pfizer-modified Yoshida correlations.

DSC data and the Pfizer-modified Yoshida correlation suggested that a reagent could be shock-sensitive and/or able to propagate an explosion. Shock (impact) sensitivity was tested by means of drop hammer experiments, performed as a series of six trials. A material’s ability to propagate an explosion was evaluated by a validated experimental method (vide infra) using fast-capture data acquisition on an accelerated rate calorimeter (ARC). In addition, traditional heat−wait−search accelerating rate calorimetry data were obtained on materials that posed a risk identified by DSC analysis.

shock-sensitive and/or potentially explosive and will require additional testing such as drop hammer and explosivity screening before being used in a Pfizer manufacturing facility. SS = log(Q DSC) − 0.72[log(TDSC − 25)] − 0.98

(1)

EP = log(Q DSC) − 0.38[log(TDSC − 25)] − 1.67

(2)

QDSC is the energy of the exotherm in cal/g, and TDSC is the onset temperature of the exotherm in °C. It is important to note that the Yoshida correlations are meant to be very conservative to ensure that all compounds that have the potential to be either shock-sensitive and/or explosive are flagged. Pfizer (as well as many other pharmaceutical companies) has taken the Yoshida correlations and applied an additional degree of conservatism to further reduce the likelihood of any false negatives so that all materials that could exhibit impact sensitivity or explosivity are thoroughly studied before their use in large-scale manufacture of active pharmaceutical ingredients (APIs) begins. Pfizer has lowered the energy threshold in the Yoshida correlation by 25%, which is shown by the “Pfizer-modified” lines in Figure 2.13 From this point forward, all references to the Yoshida correlation mean the more conservative “Pfizer-modified Yoshida correlation”. Table 1 shows the identity and structure of the 45 peptide coupling agents studied. Each sample was tested by DSC in triplicate, and the average (mean)14 total energy values of observed exotherms and left limit onset temperatures15 are reported (Tables 2−4). Further testing was carried out if the

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RESULTS AND DISCUSSION Table 2 shows DSC data for peptide coupling reagents commonly used in the scale-up of amidation reactions.16 Methanesulfonyl chloride (MsCl, entry 1)17 and p-toluenesulfonyl chloride (TsCl, entry 2)18 generate the sulfonyl esters from the corresponding carboxylic acids. Both reagents have relatively high thermal onsets at 341 and 249 °C, respectively. Neither of these reagents was flagged by either Yoshida correlation. Phosphorus oxychloride (entry 3) and oxalyl chloride (entry 4) facilitate peptide coupling reactions by converting the carboxylic acid into the corresponding acyl chloride before reaction with an amine.19 Both phosphorus oxychloride and oxalyl chloride exhibited small thermal decompositions at high temperatures (368 and 234 °C, respectively). Neither of these reagents was flagged by either Yoshida correlation. Thionyl chloride is another reagent commonly used to convert carboxylic acids to acyl chlorides. Attempts were made to obtain DSC data for thionyl chloride, 1263



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Table 1. Common Peptide Coupling Reagents

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Table 1. continued

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Table 1. continued

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Table 1. continued

common peptide couple agents that historically have been popular choices among industrial chemists.23 Both ethyl chloroformate (entry 9) and isobutyl chloroformate (entry 10) have relatively low onset temperatures of decomposition at 136 and 113 °C, respectively. Applying a 100 °C margin of safety (MOS) would impose an upper operating limit of 36 and 13 °C depending on which reagent was used. Although neither of these reagents was flagged by the Yoshida correlations, performing large-scale processes with these chloroformates above the MOS-adjusted temperatures would require additional safety testing such as thermal screening unit (TSu) data or accelerating rate calorimetry. The additional data would also be used to determine appropriate storage and handling conditions. Entries 11−13 belong to the family of quinolone-based coupling reagents. As seen in Table 2, these reagents show both high onset temperatures and relatively low exothermic decompositions. Entries 14−16 show data for the triazinebased coupling reagents. 2,4,6-Trichloro-1,3,5-triazine (TCT, entry 14) has a high onset temperature of 360 °C and a small exothermic energy of decomposition (−36 J/g). TCT is not flagged as potentially shock-sensitive or explosive by the

but it was very difficult to get reproducible results due to its high volatility. Entries 5−13 contain coupling reagents that facilitate amidations via mixed anhydride formation. Both T3P20 (entry 5) and CDI21 (entry 6) are commonly used for the scale-up of APIs in the pharmaceutical industry. CDI is inexpensive, readily available in bulk quantities, and soluble in a number of common organic solvents. Additionally, the byproducts (CO2 and imidazole) can easily be removed from the reaction mixture upon quench. n-Propylphosphonic anhydride (T3P) has recently become a popular choice among industrial process chemists for its ease of use, low epimerization of chiral centers, and availability in a range of different solvents.22 N,N′-Disuccinimidyl carbonate (NDSC, entry 7) was flagged by both Yoshida correlations (vide infra). N,N′Disuccinimidyl carbonate has a thermal onset temperature of 227 °C, well above typical reactions involving this reagent, but exhibits thermal decompositions totaling −1763 J/g. This reagent possesses the greatest thermal decomposition energy value for all reagents contained within this publication. In contrast, pivaloyl chloride (PivCl, entry 8) displayed no exothermic activity up to 400 °C. Chloroformates are also 1267



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Table 2. DSC Data for Peptide Coupling Reagents Commonly Used in Scale-up entry

reagent

1 2 3 4 5 6 7 8

MsCl TsCl POCl3 (COCl)2 T3P CDI NDSC PivCl

9 10 11 12 13 14 15 16 17 18 19

ECF IBCF EEDQ IIDQ BBDI TCT DMTMM CDMT EDCI DIC DCC

average major left limit onset (°C) 341 249 368 234 202 186 227 no observed exotherm 136 113 252 247 373 360 163 161 120 252 254

average total exothermic energy (J/g) −153 −451 −24 −47 −49 −507 −1763 no observed exotherm −344 −470 −164 −139 −93 −36 −956 −513 −549 −410 −269

Table 3. DSC Data for Phosphonium, Phosphinic Halide, Phosphate, Phosphite, and Phosphinate Reagents

Yoshida shock (S)/ explosive (E)

entry

reagent

1 2 3 4 5 6 7

PyBOP PyBrOP PyClOP PyAOP PyClU BOPCl DppCl

N/A N/A N/A N/A N/A N/A S/E N/A

8 9 10 11

N/A N/A N/A N/A N/A N/A E N/A N/A N/A N/A

DEPC DPP DPC FDPP

average major left limit onset (°C) 121 246 271 135 302 198 no observed exotherm 195 242 247 no observed exotherm

average total exothermic energy (J/g) −1020 −360 −473 −858 −328 −901a no observed exotherm −136 −94 −56 no observed exotherm

Yoshida shock (S)/ explosive (E) S/E N/A N/A E N/A N/A N/A N/A N/A N/A N/A

Exotherm continued past 400 °C, so the integrated value will be greater than −901 J/g. a

of α-stereocenters and are often employed in the discovery phase of drug development.26 PyBOP contains 1-hydroxybenzotriazole (HOBt), a known explosive material with a U.N. classification of 1.3 (fire, minor blast). PyBOP has a thermal onset of decomposition at 121 °C with an exothermic release of −1020 J/g of energy. These data are sufficient to classify PyBOP as potentially shock-sensitive and potentially explosive based on the Yoshida correlations. PyAOP contains 1-hydroxy-7-azabenzotriazole (HOAt). In similar fashion to HOBt, HOAt has been classified as a class 1.4 explosive material by U.N. shipping guidance (minor explosion hazard). PyAOP has a thermal onset at 135 °C and releases −858 J/g of energy, flagging this material as potentially explosive but not impact-sensitive. The other reagents derived from BOP, bromotrispyrrolidinophosphonium hexafluorophosphate (PyBrOP, entry 2), chlorotripyrrolidinophosphonium hexafluorophosphate (PyClOP, entry 3), chlorodipyrrolidinocarbenium hexafluorophosphate (PyClU, entry 5), and bis(2-oxo-3oxazolidinyl)phosphinic chloride (BOPCl, entry 6) were not flagged by either of the Yoshida correlations. Entries 7−11 in Table 3 are phosphorus-based reagents that facilitate amidation reactions through activation of the carboxylic acid by generation of an oxygen−phosphorus covalent bond. Diphenylphosphinic chloride (DPPCl, entry 7) and pentafluorophenyl diphenylphosphinate (FDPP, entry 11) exhibited no exothermic activity up to 400 °C. The other three reagents in this series, diethyl chlorophosphate (DEPC, entry 8), diphenyl phosphite (DPP, entry 9), and diphenyl phosphoryl chloride (entry 10), exhibited high onset temperatures at or above 195 °C with small accompanying exotherms no greater than −136 J/g. The peptide coupling reagents listed in Table 4 are uroniums, imidazolidiniums, and carbenium salts which represent a range of widely popular compounds often used in the discovery phase of pharmaceutical development and occasionally in the early development stages.27 These reagents are popular among discovery scientists due to their ability to promote amidation reactions between sterically hindered coupling partners and promote coupling without epimerization of α-stereocenters. Although these reagents are oftentimes the “go-to” reagents for pharmaceutical discovery chemists, they pose significant challenges for large-scale processes. Many of

Yoshida correlations. In contrast, 4-(4,6-dimethoxy-1,3,5triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, entry 15) displayed a thermal onset at 163 °C with an exothermic release of −956 J/g. These data are enough to flag DMTMM as potentially explosive but not impact-sensitive by the Yoshida correlations. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, entry 16) is the synthetic precursor to DMTMM. Although CDMT has a thermal onset approximately 80 °C lower than that of DMTMM, CDMT also displays about 55% of the total energy associated with the decomposition (−513 J/g). Unlike DMTMM, CDMT does not flag as potentially shock-sensitive or explosive. Finally, entries 17−19 contain data for carbodiimide-based reagents.24 Although a number of carbodiimide reagents exist for peptide couplings, the most commonly used reagents for large-scale peptide coupling reactions are N-(3(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (EDCI, entry 17), N,N-diisopropylcarbodiimide (DIC, entry 18), and N,N-dicyclohexylcarbodiimide (DCC, entry 19). None of these carbodiimde reagents flagged as potentially shock-sensitive or explosive. EDCI, in similar fashion to the two chloroformate reagents discussed above, may require some additional safety testing given its low onset temperature (120 °C) and quantity of heat released (−549 J/g). The peptide coupling reagents in Table 3 are phosphorusbased reagents that include phosphates, phosphites, phosphinates, phosphinic halides, and phosphonium salts. Entries 1−6 are reagents derived from Castro’s reagent25 ((benzotriazol-1yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, BOP). BOP is not a preferred reagent for large-scale production due to the generation of stoichiometric amounts of hexamethylphosphoramide (HMPA), a known carcinogen. Benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, entry 1) and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP, entry 4) are derivatives of BOP that do not generate HMPA. These peptide coupling reagents often suppress epimerization 1268



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explosive during the reaction, and this byproduct generation must be evaluated accordingly. Of the reagents listed in Table 4, four are derived from either HOBt or 5-chlorohydroxybenzotriazloe (5-Cl-HOBt). These include TBTU, HBTU, HCTU, and TCTU (entries 2, 3, 7, and 8, respectively). TBTU, HBTU, and TCTU all exhibit exothermic decompositions greater than −1000 J/g and are flagged as potentially explosive. TBTU and TCTU are also flagged as potentially shock-sensitive. HCTU is not flagged as potentially shock-sensitive or explosive but still exhibits a significant exothermic decomposition of −845 J/g. HATU (entry 11) and HDMA (entry 14) are derived from HOAt. Both of these reagents were flagged as potentially explosive and shock-sensitive by the Yoshida correlations and exhibited significant exothermic decompositions of −1131 and −1083 J/ g, respectively. Many reagents not derived from HOBt or HOAt listed in Table 4 also contain high-energy functional groups such as benzotriazine (TDBTU, entry 1) and N−O bonds [TSTU (entry 4), TOTU (entry 6), COMU28 (entry 10), TNTU (entry 13), and CITU29 (entry 15)]. Although many of the N−O containing reagents exhibit highly exothermic decompositions, only TOTU was flagged as potentially explosive by the Yoshida correlations. TPTU (entry 9) was flagged as potentially explosive but not shocksensitive.30 CIP (entry 5) and TFFH (entry 12) are the only two reagents in Table 4 that do not contain any high-energy functional groups. These two reagents possess higher thermal onsets and much lower exothermic energies of decomposition.

Table 4. DSC Data for Uronium, Imidazolidinium, and Carbenium Salts entry

reagent

average major left limit onset (°C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

TDBTU TBTU HBTU TSTU CIP TOTU HCTU TCTU TPTU COMU HATU TFFH TNTU HDMA CITU

114 181 173 206 225 146 149 163 124 127 161 361 216 151 181

average total exothermic energy (J/g)

Yoshida shock (S) or explosive (E)

−991 −1206 −1032 −867 −163 −838 −845 −1036 −826 −736 −1131 −209 −931 −1081 −395

S/E S/E E N/A N/A E N/A S/E E N/A S/E N/A N/A S/E N/A

the reagents listed in Table 4 are derived from HOBt or HOAt, and others contain high-energy functional groups. It is important to remember the reagents that are derived from HOBt and HOAt generate a stoichiometric amount of these byproducts from the reaction in which they are used. If the peptide reagent itself is not classified as an explosive or impactsensitive, HOBt and HOAt derivatives will generate a known

Figure 3. Yoshida correlations for shock sensitivity. 1269



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at least one DSC experiment flag as potentially explosive, but their average onset temperature versus average total exothermic energy fell below the Pfizer-modified correlation. In a similar fashion to the shock sensitivity experiments, the decision was made to test all reagents for potential Class 1 explosive properties where at least one DSC experiment fell above the Pfizer-modified Yoshida correlation. The Koenen test is one of the four tests described by the United Nations Transport of Dangerous Goods document and is used to understand a material’s sensitiveness to the effect of intense heat under confinement. These tests are expensive and time-consuming and require large quantities of materials (typically hundreds of grams). However, a fast and smallscale explosivity screening test method was reported in 2004 by Bodman and Chervin32 that utilized a modified ARC equipped with a pressure transducer capable of detecting and measuring incredibly rapid pressure events (10 000 data points per second). In a similar fashion, an ARC was equipped with a fast data capture pressure transducer to screen the peptide reagents that were flagged as potentially explosive. This instrument was validated by studying a series of compounds that are known to exhibit explosive properties. The ScanARC is a rapid screening tool that uses only 1 g of material, and experiments are complete within 3 h. In order to meet the criteria for a potential Class 1 explosive, a material must exhibit a maximum pressure rate (dP/dt) of >20 000 bar/min in the Pfizer ScanARC test. Any materials that exhibit pressure rates of >20 000 bar/min will undergo additional U.N. Series 1 and Series 3 testing. As seen in Table 6, TDBTU (entry 1) underwent decomposition with a maximum rate of pressure rise of 14 900 bar/min. This rate of pressure rise in the Pfizer ScanARC instrument would not classify TDBTU as a potential Class 1 explosive; therefore, Pfizer did not carry out any additional U.N. Series 1 or Series 3 testing. The other 11 reagents that were flagged by DSC as potentially Class 1 explosives were tested by ScanARC. None of the reagents tested exhibited rates of pressure rise >20 000 bar/min and, therefore, were not subjected to additional U.N. testing. It is important to note that although none of these reagents was subjected to additional testing for explosive properties, they are all highly energetic and demand respect. A traditional ARC experiment using a heat−wait−search technique provides high-quality thermal data which can be used to determine accurate thermal onset temperatures. Additionally, traditional ARC data can be phi-corrected33 to determine the adiabatic temperature rise for the thermal decomposition as well as the onset temperature for a large quantity of material with little heat transfer capability (phi = 1, adiabatic). Although many companies apply a MOS correction of 100 °C to DSC onset temperatures, they typically apply a smaller MOS (30−50 °C) to phi-corrected thermal onsets from a traditional ARC experiment.34 Even though the thermal data can be phi-corrected, the rates of pressure rise cannot be phi-corrected to model large-scale decompositions. Due to the fast temperature ramp used (5 K/min) in the ScanARC, ScanARC data are not used for thermal onset determination. However, the fast temperature ramp allows ScanARC experiments to provide very useful information on a material’s ability to generate dangerous amounts of gas at very high rates during an unintended decomposition event. Traditional heat−wait−search ARC testing was performed on TBTU and all of the reagents that flagged as potentially shock-sensitive and/or explosive. As seen in Table 7, three

Figure 3 shows the DSC data plotted against the Yoshida correlations. The red circles in Figure 3 represent reagents where at least one of the three DSC experiments flagged as potentially shock-sensitive (above the Pfizer-modified Yoshida correlation). The DSC data flagged seven reagents as potentially shock-sensitive: N,N′-disuccinimidyl carbonate (NDSC), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-(3,4-dihydro-4-oxo-1,2,3benzotriazin-3-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TDBTU), N,N,N′,N′-tetramethyl-O-(benzotriazol-1yl)uronium tetrafluoroborate (TBTU), O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TCTU), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexa fluor oph osphate (HA TU), an d 1 [(dimethylamino)(morpholino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluorophosphate (HDMA). TBTU has been examined previously and shown to exhibit explosive properties, and therefore, it was not tested further in our studies.7 The other six reagents were subjected to a 60J impact (dropping a 10 kg weight from a height of 60 cm). The United Nations Recommendations on the Transport of Dangerous Goods31 distinguishes between “explosion” and “decomposition”. Explosions are characterized by a weak to strong report or inflammation. Decompositions are characterized by change of color or odor (without flame or explosion). Each material tested underwent six trials, and the data can been seen in Table 5. Table 5. Results from Drop Hammer Experiments entry

reagent

decomposition

explosion

1 2 3 4 5 6

TDBTU HDMA HATU TCTU PyBOP NDSC

yes yes yes yes no no

no no no no no no

Of the six reagents that were tested in Table 5, TDBTU (entry 1), HDMA (entry 2), HATU (entry 3), and TCTU (entry 4) all exhibited clear signs of decomposition, but not explosions, at 60 J. None of the reagents showed signs of smoke, odors, inflammation, or audible report. Although discoloration at 60 J may not be enough to preclude the use of these reagents in early development, additional risk assessments should be undertaken to understand if these decomposition events could initiate other decomposition events for any given process, especially as the scale of a process increases to pilot and commercial scale. Of the 45 reagents that were tested, 12 had at least one DSC experiment that was flagged as potentially explosive. The DSC data for all 45 reagents plotted against the Yoshida correlations can be seen in Figure 4. The red circles represent reagents where at least one of the three DSC experiments flagged as potentially explosive (falling above the Pfizer-modified Yoshida correlation). Unlike the Yoshida correlation for shock sensitivity, where no reagents fell above the unmodified correlation, one reagent, N,N′-disuccinimidyl carbonate (NDSC), fell significantly above the unmodified correlation for explosivity. Of the other 10 reagents, 6 fell between the Pfizer-modified Yoshida correlation and the unmodified Yoshida correlation. These were PyBOP, TBTU, HBTU, TCTU, HATU, and HDMA. The remaining four reagents had 1270



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Figure 4. Yoshida and Pfizer-modified Yoshida correlations for explosivity.

Table 6. Results from an Explosivity Screen

Table 7. Accelerating Rate Calorimetry Data

entry

reagent

max dP/dt (bar/min)

potentially Class 1 explosive (yes/no)

1 2 3 4 5 6 7 8 9 10 11 12

TDBTU HDMA HATU TCTU PyBOP NDSC TOTU HBTU PyAOP DMTMM TNTU TPTU

14900 5400 5300 9170 1030 10270 4860 3970 4780 3630 400 5650

no no no no no no no no no no no no

entry

reagents had phi-corrected thermal onsets below 100 °C. These include TDBTU (87 °C, entry 1), DMTMM (77 °C, entry 10), and TPTU (97 °C, entry 12). Low phi-corrected thermal onsets can pose particular challenges with respect to storage, transportation, and any reaction that requires elevated temperatures. Table 7 also shows each material’s TD2435 value.

a

1271

reagent

thermal onseta (°C)

1

TDBTU

87

2 3

HDMA HATU

126 126

4 5 6 7 8 9 10 11

TCTU PyBOP NDSC TOTU HBTU PyAOP DMTMM TNTU

117 106 133 104 138 106 77 130

12

TPTU

97

13

TBTU

133

TD24 (°C) not able to be determinedb 117 not able to be determinedb 107 97 105 95 119 75 68 not able to be determinedb not able to be determinedb 114

ATRa (°C) >615 >464 >315 >590 >282 >552 >483 >478 >467 210 >518 >228 >513

Values are phi-corrected. bAutocatalytic behavior suspected.



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reagents derived from HOBt because these reagents generate a stoichiometric amount of HOBt, a known explosive and shocksensitive material. The complete list of reagents can be seen in Figure 5 grouped into three categories based the thermal stability data reported in this publication.

This experimentally determined value represents the temperature from which the decomposition reaction requires 24 h to reach its peak rate. A low TD24 value can also pose greater risks for storage, transportation, drying operations, and reactions carried out above ambient temperature. The lowest TD24 value of 68 °C belongs to DTMM (entry 10). This reagent also possesses a low phi-corrected thermal onset (vide supra). Taken together, these data suggest that extended drying DMTMM at elevated temperatures could pose a safety risk. For this reason, DMTMM is usually prepared in situ from CDMT and N-methylmorpholine. Four of the reagents listed in Table 6 exhibited autocatalytic behavior, which precluded an accurate determination of TD24 (TDBTU, entry 1; HATU, entry 3; TNTU, entry 11; and TPTU, entry 12). Reagents that exhibit autocatalytic behavior should be used with extreme caution. Autocatalytic decompositions are characterized by sudden heat evolution, preceded by an initiation event that is oftentimes not well-understood. These violent decompositions can also be initiated by small trace impurities, such as metals or other high-energy organic compounds.36 Given these factors, they are often perceived as highly unpredictable, and materials that exhibit these properties should be treated with appropriate caution. Another valuable data point determined from heat−wait− search ARC is a material’s adiabatic temperature rise (ATR). As a large mass of material decomposes in a runaway reaction, it loses the ability to effectively exchange heat with the surroundings. In this pseudoadiabatic system, the energy released by the decomposition reaction is used to increase the material’s temperature. Generally seen as a “worst case scenario”, a material’s ATR is a convenient method to assess the severity of a thermal runaway. All of the reagents listed in Table 6 exhibited ATRs above 200 °C. TDBTU has an ATR of >615 °C37 and by far has the largest ATR of the reagents studied in this paper. For reference, the phi-corrected ATR of 2,4,6-trinitrotoluene (TNT) was reported to be 1363.5 °C.38

Figure 5. Pfizer peptide reagent selection guide from Process Safety.39

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EXPERIMENTAL SECTION Differential Scanning Calorimetry. All DSC measurements were performed on a Mettler-Toledo differential scanning calorimeter. All materials were purchased immediately before the test. Reagents were purchased at a minimum of 95% purity as stated by the vendor. Each reagent was tested in triplicate. For consistency, all samples were loaded under a nitrogen atmosphere. Approximately 3−5 mg of solid and 5− 10 mg of liquid was weighed into a 40 μL gold-plated highpressure DSC test cell system consisting of a crucible, rupture disk, and lid. The test cell was then sealed using a Jossi crimper. The test method included the following: isothermal hold at 30 °C for 10 min followed by ramp from 30 to 400 °C at 5 °C/min. Sample cells were reweighed after analysis to ensure no samples leaked during the test (max gain/loss ±5%). Drop Hammer. Solid samples were tested following the BAM Fallhammer test method as described in U.N. Recommendations on the Transport of Dangerous Goods, Manual of Tests and Criteria, Section 13.4.2 (Test 3 (a) (ii)). The sample was charged to the steel cylindrical test cell using a 40 μL scoop, and the closed sample cell was placed in the locating ring on the anvil. The desired weight (usually 10 kg) is raised to a height of 60 cm and locked in place. All testing began at 60 J. The lights in the room were extinguished, and the weight released using the pull cord mechanism. Observations were made to detect audible reports, visible sparks, or flames upon impact of the weight. After the lights were turned on, the test cell was opened and inspected for signs of sample discoloration or decomposition. The test consisted of 6 trials in accordance with Test 3 (a) (ii). Liquid samples were not tested. Explosivity Screen (ScanARC). A 1/4 in. Swagelok nut and ferrule were swaged onto a Hastelloy ARC test cell with a side clip and 1/4 in. stem. Approximately 1 g of sample was charged to the test cell, and then the test cell was swaged to the pressure fitting on the lid of the apparatus. The thermocouple and guard heater were secured in place, and the top heater assembly was lowered carefully into the lower heater assembly

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CONCLUSIONS In conclusion, 45 peptide coupling reagents commonly used in the generation of pharmaceutical intermediates and APIs were first examined by differential scanning calorimetry. The data were then correlated to the Yoshida diagrams for explosivity and shock sensitivity in an effort to determine which of these reagents would require additional safety testing. A total of seven reagents were flagged as potentially shock-sensitive. Of these seven reagents (TDBTU, TBTU, HDMA, HATU, TCTU, PyBOP, and NDSC), four (TDBTU, HDMA, HATU, and TCTU) exhibited discoloration during the drop hammer experiments. A total of 12 reagents were flagged as potentially explosive (TDBTU, HDMA, HATU, TCTU, PyBOP, NDSC, TOTU, HBTU, PyAOP, DMTMM, TNTU, and TPTU). Of these 12 reagents, none tested as potentially Class 1 explosive by ScanARC analysis. Traditional heat− wait−search ARC testing was performed on TBTU and all of the reagents that flagged as potentially shock-sensitive and/or explosive. All of the reagents studied had large ATR values, and some (TDBTU, HATU, TNTU, and TPTU) showed potentially autocatalytic decomposition behavior. The concept of inherently safer process design would drive teams to choose reagents less likely to cause safety concerns before the development of large-scale chemical processes. In the spirit of inherently safer process design, Pfizer has recently taken the stance not to develop processes that employ amide coupling 1272



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(4) Peptide Therapeutics Market: Global Industry Analysis, Size, Share, Growth, Trends and Forecast 2012−2018; Transparency Market Research, 2012. (5) Jursic, B. S.; Zdravkovski, Z. A Simple Preparation of Amides from Acids and Amines by Heating of Their Mixture. Synth. Commun. 1993, 23, 2761. (6) Perreux, L.; Loupy, A.; Volatron, F. Solvent-Free Preparation of Amides From Acids and Primary Amines Under Microwave Irradiation. Tetrahedron 2002, 58, 2155. (7) Wehrstedt, K. D.; Wandrey, P. A.; Heitkamp, D. Explosive Properties of 1-hydroxybenzotriazoles. J. Hazard. Mater. 2005, 126, 1. (8) Dunetz, J. R.; Magano, J.; Weisenburger, G. A. Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals. Org. Process Res. Dev. 2016, 20, 140. (9) (a) Kidam, K.; Sahak, H. A.; Hassim, M. H.; Shahlan, S. S.; Hurme, M. Inherently Safer Design Review and Their Timing During Chemical Process Development and Design. J. Loss Prev. Process Ind. 2016, 42, 47. (b) Kletz, T.; Amyotte, P. Process Plants: A Handbook for Inherently Safer Design; CRC Press: Boca Raton, FL, 1998. (10) Adams, J. P.; Alder, C. M.; Andrews, I.; Bullion, A. M.; Campbell-Crawford, M.; Darcy, M. G.; Hayler, J. D.; Henderson, R. K.; Oare, C. A.; Pendrak, I.; Redman, A. M.; Shuster, L. E.; Sneddon, H. F.; Walker, M. D. Development of GSK’s Reagent Guides − Embedding Sustainability into Reagent Selection. Green Chem. 2013, 15, 1542. (11) Wunderlich, B. Thermal Analysis; Academic Press: New York, 1990; p 137. (12) Wada, Y.; Foster, N.; Yoshida, T. Safety of Reactive Chemicals and Pyrotechnics; Elsevier Science, 1995. (13) The 25% conservation factor was determined after analysis of the original Yoshida report and our own internal analysis of DSC data. (14) The data ranges for the peptide coupling reagents were 5% from the mean value. Many were less than 2% from mean. Any data point that was greater than 10% from the mean was repeated. (15) Pfizer uses left-limit onset temperatures to report a material’s “thermal onset 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. (16) All of the DSC data contained herein are the average of three consecutive experiments. The Supporting Information contains a representative DSC scan of one of the three experiments. (17) (a) Norris, T.; VanAlsten, J.; Hubbs, S.; Ewing, M.; Cai, W.; Jorgensen, M. L.; Bordner, J.; Jensen, G. O. Commercialization and Late-Stage Development of a Semisynthetic Antifungal API: Anidulafungin/d-Fructose (Eraxis). Org. Process Res. Dev. 2008, 12, 447. (b) Kobayashi, T.; Masui, Y.; Goto, Y.; Kitaura, Y.; Mizutani, T.; Matsumura, I.; Sugata, Y.; Ide, Y.; Takayama, M.; Takahashi, H.; Okuyama, A. Practical Large-Scale Synthesis of Cefmatilen, A New Cephalosporin Antibiotic. Org. Process Res. Dev. 2004, 8, 744. (18) Haddad, N.; Qu, B.; Lee, H.; Lorenz, J.; Varsolona, R.; Kapadia, S.; Sarvestani, M.; Feng, X.; Busacca, C. A.; Hebrault, D.; Rea, S.; Schellekens, L.; Senanayake, C. H. PAT Application in the Expedited Development of a Three-Step, One-Stage Synthesis of the Dipeptide Intermediate of HCV Protease Inhibitor Faldaprevir. Org. Process Res. Dev. 2015, 19, 132. (19) (a) Tone, H.; Matoba, K.; Goto, F.; Torisawa, Y.; Nishi, T.; Minamikawa, J.-i. Progress in the Synthesis of OPC-15161: Easy Access to Dioxygenated Pyrazine N-Oxide Structure. Org. Process Res. Dev. 2000, 4, 312. (b) Eisenbeis, S. A.; Chen, R.; Kang, M.; Barrila, M.; Buzon, R. An Improved Synthesis of 4-(1-Piperazinyl)benzo[b]thiophene Dihydrochloride. Org. Process Res. Dev. 2015, 19, 244 and all associated references contained within ref 8. (20) For a review of T3P chemistry, see: Vishwanatha, T. M.; Panguluri, N. R.; Sureshbabu, V. V. Propanephosphonic Acid Anhydride (T3P®) - A Benign Reagent for Diverse Applications Inclusive of Large-Scale Synthesis. Synthesis 2013, 45, 1569−1601. For recent examples, see: (a) Dunetz, J. R.; Berliner, M. A.; Xiang, Y.;

and secured in place. The test commenced, and the guard heaters were set so that they delivered enough power to heat the test cell at 5 K/min. The heater power was adjusted throughout the test to maintain a heating rate of 5 K/min. Heating was stopped either when the sample temperature reached 400 °C, the pressure reached 100 bar, or through user intervention. Accelerating Rate Calorimetry. A Hastelloy ARC test cell incorporating a bottom thermocouple clip and 1/4 in. stem was weighed and the mass recorded. A 1/4 in. Swagelok nut and ferrule were swaged onto the stem, and the test cell was reweighed and the mass recorded. The material under study (ca. 2 g in this case) was charged to the test cell, and the cell was reweighed and the mass recorded. Samples were tested using a heat−wait−search method starting at 40 °C and heating in 5 K increments to a maximum temperature of 350 °C or a maximum pressure of 100 bar or user intervention. When one of the above test limits was reached, the test cell and heater assembly were cooled with an air line operated automatically by a solenoid valve. Once the test cell cooled to the desired temperature, the final pressure was noted. The cell was reweighed and the mass recorded. Phi corrections used the mass of the Hastelloy test cell but not the mass of the fittings.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.8b00193. Representative DSC scans for each reagent and all data from drop hammer tests, explosivity screens, and ARC experiments (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: jeffrey.sperry@pfizer.com. ORCID

Jeffrey B. Sperry: 0000-0003-0365-5646 Richard Barnhart: 0000-0002-7666-8942 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge Charles Santa Maria, Iain Gladwell, Clare Crook, and Jerry Weisenburger for helpful discussions. C.J.M. acknowledges support from the Pfizer Summer Internship Program.

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REFERENCES

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The DSC of COMU reported by Albericio was 160 °C versus 128 °C in this publication. The method used by Albericio included a faster ramp of 10 °C/min, whereas Pfizer uses a 5 °C/min ramp. (29) deGruyter, J. N.; Malins, L. R.; Wimmer, L.; Clay, K. J.; LopezOgalla, J.; Qin, Y.; Cornella, J.; Liu, Z.; Che, G.; Bao, D.; Stevens, J. M.; Qiao, J. X.; Allen, M. P.; Poss, M. A.; Baran, P. S. CITU: A Peptide and Decarboxylative Coupling Reagent. Org. Lett. 2017, 19, 6196−6199. (30) Although TPTU was not flagged by the Pfizer-modified Yoshida correlation for shock sensitivity, the sharp peak in the DSC trace (see Supporting Information) prompted drop hammer testing. TPTU exhibited discoloration at 60 J with no evidence of flame or audible noise above background noise. (31) UN Recommendations on the Transport of Dangerous Goods. Manual of Tests and Criteria, 5th revised ed.; United Nations: New York and Geneva, 2009. (32) Bodman, G. T.; Chervin, S. Use of ARC in screening for explosive properties. J. Hazard. Mater. 2004, 115, 101−105. (33) Wilcock, E.; Rogers, R. L. A review of the phi factor during runaway conditions. J. Loss Prev. Process Ind. 1997, 10, 289−302. (34) Usually depends on internal guidance and may differ between companies. (35) TD24 is defined as the temperature at which a material’s time-tomaximum rate under adiabatic conditions (TMRad) is 24 h and is a conservative value based on zero-order kinetics. (36) Stoessel, F. Thermal Safety of Chemical Processes: Risk Assessment and Process Design; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2008; pp 311−331. (37) For the materials containing the notation “>”, the ARC experiment ended without the exotherm reaching completion. It is assumed that if the test was allowed to continue, the measured ATR would be greater than the value reported. (38) Zhang, C.; Jin, S.; Ji, J.; Jing, B.; Bao, F.; Zhang, G.; Shu, Q. Thermal hazard assessment of TNT and DNAN under adiabatic condition by using accelerating rate calorimeter (ARC). J. Therm. Anal. Calorim. 2018, 131, 89−93. (39) This guide is only intended to be used by professionally trained chemists and engineers. Each process requires independent analysis by fully trained process safety professionals.

Verbeek, M.; Fawzy, N.; Leo, G. C.; Winters, M. P.; Kang, F.-A.; Kolpak, M.; Beauchamp, D. A.; Lanter, J. C.; Russell, R. K.; Sui, Z.; Vanbaelen, H. Lab-Scale Preparation of a Novel Cyclopenta[b]furan Chemokine Receptor Antagonist. Org. Process Res. Dev. 2014, 18, 1630−1640. (m) Funel, J.-A.; Brodbeck, S.; Guggisberg, Y.; Litjens, R.; Seidel, T.; Struijk, M.; Abele, S. Diastereospecific Enolate Addition and Atom-Efficient Benzimidazole Synthesis for the Production of L/ T Calcium Channel Blocker ACT-280778. Org. Process Res. Dev. 2014, 18, 1674−1685. (n) Chen, J.; Chen, T.; Hu, Q.; Püntener, K.; Ren, Y.; She, J.; Du, Z.; Scalone, M. Practical Asymmetric Hydrogenation-Based Synthesis of a Class-Selective Histone Deacetylase Inhibitor. Org. Process Res. Dev. 2014, 18, 1702−1713. (o) Mangion, I. K.; Chen, C.; Li, H.; Maligres, P.; Chen, Y.; Christensen, M.; Cohen, R.; Jeon, I.; Klapars, A.; Krska, S.; Nguyen, H.; Reamer, R. A.; Sherry, B. D.; Zavialov, I. Enantioselective Synthesis of an HCV NS5a Antagonist. Org. Lett. 2014, 16, 2310− 2313. (p) Littler, B. J.; Aizenberg, M.; Ambhaikar, N. B.; Blythe, T. A.; Curran, T. T.; Dvornikovs, V.; Jung, Y. C.; Jurkauskas, V.; Lee, E. C.; Looker, A. R.; Luong, H.; Martinot, T. A.; Miller, D. B.; NeubertLangille, B. J.; Otten, P. A.; Rose, P. J.; Ruggiero, P. L. Development of a Manufacturing Process for an HCV Protease Inhibitor Candidate Molecule. Org. Process Res. Dev. 2015, 19, 270−283 and all associated references contained within ref 8. (25) Castro, B.; Dormoy, J. R. Reactions des sels de trisdimethylamino(pseudo)halophosphonium sur les acides carboxyliques. Tetrahedron Lett. 1973, 14, 3243−3246. (26) (a) Coste, J.; Le-Nguyen, D.; Castro, B. PyBOP®: A new peptide coupling reagent devoid of toxic by-product. Tetrahedron Lett. 1990, 31, 205−208. (b) Wang, W.; McMurray, J. S. A selective method for the preparation of primary amides: Synthesis of Fmoc-l-4carboxamidophenylalanine and other compounds. Tetrahedron Lett. 1999, 40, 2501−2504. (27) (a) Faucher, A.-M.; Bailey, M. D.; Beaulieu, P. L.; Brochu, C.; Duceppe, J.-S.; Ferland, J.-M.; Ghiro, E.; Gorys, V.; Halmos, T.; Kawai, S. H.; Poirier, M.; Simoneau, B.; Tsantrizos, Y. S.; LlinàsBrunet, M. Synthesis of BILN 2061, an HCV NS3 Protease Inhibitor with Proven Antiviral Effect in Humans. Org. Lett. 2004, 6, 2901− 2904. (b) Karlsson, S.; Sörensen, J. H. Selection and Development of a Route for Cholesterol Absorption Inhibitor AZD4121. Org. Process Res. Dev. 2012, 16, 586−594. (c) Andrews, D. M.; Arnould, J.-C.; Boutron, P.; Délouvrie, B.; Delvare, C.; Foote, K. M.; Hamon, A.; Harris, C. S.; Lambert-van der Brempt, C.; Lamorlette, M.; Matusiak, Z. M. Fischer synthesis of isomeric thienopyrrole LHRH antagonists. Tetrahedron 2009, 65, 5805−5816. (d) O’Shea, P. D.; Chen, C.-y.; Gauvreau, D.; Gosselin, F.; Hughes, G.; Nadeau, C.; Volante, R. P. A Practical Enantioselective Synthesis of Odanacatib, a Potent Cathepsin K Inhibitor, via Triflate Displacement of an αTrifluoromethylbenzyl Triflate. J. Org. Chem. 2009, 74, 1605−1610. (e) Fei, Z.; Kong, W.; Wang, H.; Peng, J.; Sun, F.; Yin, Y.; Bajwa, J.; Jiang, X. A Scalable Synthesis of a Hydroxamic Acid LpxC Inhibitor. Org. Process Res. Dev. 2012, 16, 1436−1441. (f) Roemmele, R. C.; Christie, M. A. Development and Scale-Up of an Optimized Route to the Peptide Boronic Acid, CEP-18770. Org. Process Res. Dev. 2013, 17, 422−426. (g) Pikul, S.; Cheng, H.; Cheng, A.; Huang, C. D.; Ke, A.; Kuo, L.; Thompson, A.; Wilder, S. Synthetic Process Development of BMS-599793 Including Azaindole Negishi Coupling on Kilogram Scale. Org. Process Res. Dev. 2013, 17, 907−914. Remarchuk, T.; StJean, F.; Carrera, D.; Savage, S.; Yajima, H.; Wong, B.; Babu, S.; Deese, A.; Stults, J.; Dong, M. W.; Askin, D.; Lane, J. W.; Spencer, K. L. Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-up. Org. Process Res. Dev. 2014, 18, 1652−1666. (h) Carpino, L. A. 1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive. J. Am. Chem. Soc. 1993, 115, 4397−4398. (i) Carpino, L. A.; El-Faham, A.; Albericio, F. Racemization studies during solid-phase peptide synthesis using azabenzotriazole-based coupling reagents. Tetrahedron Lett. 1994, 35, 2279−2282. (28) El-Faham, A.; Funosas, R. S.; Prohens, R.; Albericio, F. COMU: A safer and more effective replacement for benzotriazole-based uronium coupling reagents. Chem. - Eur. J. 2009, 15, 9404−9416. 1275


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