Addressing Process Safety Hazards: Replacement of para

Chapter 11

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Addressing Process Safety Hazards: Replacement of para-Methoxybenzyl Chloride Leads to a Safer and Shorter Route Oliver R. Thiel,* John R. Huckins, Derek B. Brown, Eric A. Bercot, John T. Colyer, Bobby Riahi, Rob R. Milburn, Steve M. Shaw, and Joe Tomaskevitch Amgen, Chemical Process Research and Development, One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States *E-mail: [email protected]

Access to kilogram amounts of 1H-benzimidazol-2-yl(4hydroxyphenyl)methanone (1) was required in support of a development program. The initial synthesis used 4-methoxybenzyl chloride (PMBCl, 2) as a reagent to set the protecting group, which required a careful hazard analysis prior to use in the first generation synthesis of 1. The hazards associated with PMBCl made it a non-viable choice for long-term supplies, and therefore alternative chemistry was developed with a special emphasis on safety and efficiency. The final synthesis proceeds in two chemical steps with a high overall yield (80%) and the available data support the safety of the developed process.

Introduction A key priority for early phase process research and development is the delivery of kilogram amounts of drug substance under aggressive timelines. Depending on the molecular complexity of the target, the route used by the Medicinal Chemistry groups can serve as a ‘fit for purpose’ platform to enable early deliveries. Primary focus is then placed on addressing potential processing hazards, while ideally also simplifying workups and isolations. A process hazard analysis is routinely conducted and hazardous reaction steps or reagents are appropriately managed. Experience gained from the first delivery feeds into © 2014 American Chemical Society In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


prioritization of next generation route selection efforts, in which hazardous reagents and steps are eliminated to the greatest extent possible. Support of a recent development program at Amgen required access to kilogram amounts of 1H-benzimidazol-2-yl(4-hydroxyphenyl)methanone (1) as a key intermediate. The Medicinal Chemistry route to this building block relied on a three step sequence (Scheme 1). 4-Methoxybenzyl chloride (PMBCl, 2) was employed to install a protecting group on ethyl 4-hydroxybenzoate (3) affording intermediate 4. The key carbon-carbon bond formation was accomplished using transiently protected, and then deprotonated benzimidazole (5) (1). Towards this end benzimidazole was protected as the N-diethoxymethyl derivative using triethylorthoformate. Addition of electrophile 4, followed by in situ deprotonation with lithium diisopropylamide (LDA) at low temperature and an aqueous acidic quench afforded intermediate 6. The final deprotection of the 4-methoxybenzyl group was accomplished using trifluoroacetic acid in dichloromethane. Overall this efficient sequence provided the target intermediate in 65% yield (2).

Scheme 1. Medicinal Chemistry route to key intermediate (1).

Hazard Evaluation of 4-Methoxybenzylchloride and Screening of PMBCl Stabilizers The 4-methoxybenzyl (PMB) group is a popular protecting group for alcohols and phenols due to its relative ease of installation and cleavage. It was chosen by our discovery colleagues over other alternatives since it could be easily cleaved under acidic conditions. The alternative use of a benzyl protecting group, followed by hydrogenative removal led to side reactions. The thermal hazards of PMB-Cl 270 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


have been described in the literature (3, 4), and recently a more detailed study was published (5). Several safety incidents involving inadequate handling or storage have been reported with this reagent, which are thought to be the result of an uncontrolled exothermic cationic polymerization with concomitant release of HCl gas. This knowledge led us to further evaluate the overall hazard potential of PMB-Cl prior to use on kilogram scale. PMB-Cl decomposes in a runaway polymerization that is triggered by traces of HCl. The literature data suggests that unstabilized PMB-Cl can undergo autocatalytic decomposition within hours at temperatures of as low as 35 °C. Limited stability of at least 9 days at room temperature (25 °C) was achieved by storing PMB-Cl over solid potassium carbonate to scavenge trace acid (5). Our own results corroborate and extend these findings. An interesting observation was made with regards to the effectiveness of stabilizers. Most commercial samples of PMB-Cl are stabilized with potassium carbonate. The efficiency of this heterogenous stabilizer is impacted by the minimal solubility and more efficient scavenging was observed in stirred systems (5). In our studies, exothermic decomposition and pressure build-up was detected at 66 °C using accelerating-rate-calorimetry (ARC) (Figure 1) (6). Conducting the ARC experiment using a stirred sample cell in the presence of additional spiked potassium carbonate did not increase the exotherm onset temperature. It was however noted that the time to maximum rate, defined as the time it takes for the decomposition reaction to reach its maximum rate from its onset temperature, could be delayed by having a reservoir of scavenging agent available (Table 1) (7). We noted significant differences in onset temperature and time to max rate depending upon the source of the PMB-Cl, suggesting that all lots should be examined upon receipt. The improved stability in stirred samples as compared to unstirred samples is a result which can be relatively easy rationalized for a heterogeneous scavenger due to mass-transfer limitations. While this finding is scientifically interesting, it has limited practical relevance, since storage of the material is usually performed without stirring. Samples of material with the homogenous stabilizer amylene are also commercially available, and it was of interest to compare the efficiency of the stabilizers. Somewhat unexpectedly, amylene is not more efficient in delaying exothermic decomposition of PMB-Cl. Exothermic decomposition occurred as low as 56 °C (Figure 2, Table 1) (8). Similar to the previous trends, an extension in time to maximum rate could be achieved by simply adding larger amounts of the scavenger (Table 1). No conclusive recommendation can be made to which scavenger is preferred (homogenous or heterogeneous) based on these data. Ultimately neither scavenger led to a stabilization that would justify the safe usage of PMB-Cl on very large scale. Together with the previously published results (5), we concluded that PMB-Cl could be used on limited scale with the following precautions: • • • •

purchase of fresh reagent as needed in limited quantities testing of each batch for thermal stability use of a stabilizer to minimize potential of exothermic decomposition cold storage of reagent (2–8 °C) 271 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


Figure 1. ARC-trace of PMB-Cl stabilized with potassium carbonate.

Table 1. Summary of ARC results for commercial PMB-Cl samples. Additive

Onset T (°C)

Time to max rate (min)c

Max T rate (°C/min)

Max P rate (bar/min)

Energy (J/g)

-

-

76

47

29

65.5

221

1a

+

3.4 wt% K2CO3

71

66

24

46.6

234

1a

+

10 wt% K2CO3

66

137

14

28.8

246

2b

-

-

66

67

20

28.9

247

2b

-

0.57 wt% amylene

71

55

20

29.9

237

2b

-

5.8 wt% amylene

56

142

8

12.4

273

Sample

Stirring

1a

a

Supplier A, stabilized with solid potassium carbonate. b Supplier B, stabilized with amylene. c Indicates the time it takes for the sample to reach its maximum temperature rate under adiabatic conditions starting from the onset temperature.

272 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


Figure 2. ARC-trace of PMB-Cl stabilized with amylene.

Consequently the Medicinal Chemistry route (Scheme 1) was scaled up without major issues (~ 5-10 kg batch size for the synthesis of intermediate 4). The yield for the protection step was within the previous range (96%), while slightly diminished yields (56-58%), were obtained for the nucleophilic addition step forming ethyl ester 4. The conditions for the deprotection were modified compared to the Medicinal Chemistry approach, in order to avoid use of the less environmentally benign solvent (dichloromethane) and acid (trifluoroacetic acid) (vide infra).

Second Generation Route and Process Safety Assessment Since our route scouting towards a completely alternative bond disconnection strategy was not successful, an improved version of the original route was sought. Due to the established usefulness of intermediate 6, it was retained as an intermediate in the synthesis towards the key building block 1. Emphasis in a second generation route focused on the following priorities: • • •

replacement of PMB-Cl as a reagent increasing the robustness of the nucleophilic addition step improving conditions for the deprotection of the PMB-group

Toward these goals a three step synthesis (four isolations) of 1 was developed (Scheme 2).



Scheme 2. Second generation synthesis of 1 Replacement of PMBCl with PMB Alcohol It was proposed that the use of PMB-Cl could be avoided by reversing the functionalities of the starting materials. Mechanistically the safety hazards associated with PMB-Cl are due its properties as highly reactive electrophile. Therefore it was preferred leveraging a reaction that would install the PMB-group as a nucleophile. Towards this end 4-methoxybenzyl alcohol (7) could be coupled in a simple nucleophilic aromatic substitution reaction with 4-fluorobenzonitrile (8) (Scheme 2). The nitrile group was chosen over the ester as a carbonyl synthon because its electronic induction effect was expected to facilitate the nucleophilic aromatic substitution with PMB-OH and may allow running the ketone formation reaction at a higher temperature. Compared to esters, nitriles usually show less prevalence for formation of the overaddition products (tertiary alcohols or amines), since the intermediate metal amide formed after the first addition step is relatively stable (9, 10). Process Optimization A screen of solvents (DMF, DME, DMAc, NMP, THF) and bases (potassium phosphate, cesium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide) led to the identification of N-methylpyrrolidine (NMP) and solid potassium hydroxide as the ideal combination when conversion, processability and cost were considered. Potassium phosphate and potassium carbonate led to low conversions in a variety of solvents. Cesium carbonate provided acceptable 274 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


results, but was deprioritized for cost and green chemistry considerations. Sodium and potassium tert-butoxide gave nearly complete conversions, but offered no distinct advantages over the simpler hydroxide bases. Reactions in polar aprotic solvents achieved higher conversion as compared to the reactions in the ethereal solvents, presumably due to solubility reasons. Ultimately, NMP was identified as a preferred solvent. It provided the highest solubility of the product and thereby allowed the reaction to be performed at high concentration while maintaining efficient stirring. Potassium hydroxide was preferred over sodium hydroxide based on the enhanced solubility of the byproduct fluoride salts in water. The use of aqueous hydroxide bases led to slower reactions and formation of up to 10% (HPLC area %) of the corresponding primary amide from the nitrile as a substantial byproduct. Under the optimized conditions 4-methoxybenzyl alcohol (7) was added to a suspension of solid potassium hydroxide in NMP, followed by addition of 4-fluorobenzonitrile (8). The reaction was rapid even at room temperature (2-3 h) and the product could be isolated by crystallization by the simple addition of water, affording 9 in high yield (92%) and purity (99.7 HPLC area %, 97 wt%). The safety of this process was evaluated by performing differential scanning calorimetry (DSC) of reaction mixtures at different stages. The mixture of potassium hydroxide and 7 in NMP showed exothermic activity only between 100-107 °C, thereby assuring a large effective safety margin over the process temperature (< 30 °C). Further evaluation of the second step allowed us to get a more detailed understanding of the intermediates and impurities formed in this reaction. The original conditions for protection employed triethylorthoformate in toluene and benzenesulfonic acid as a catalyst to afford intermediate 10 (Figure 3). The mixture’s equilibrium was shifted towards product formation by azeotropic distillation with toluene. Monitoring of the reaction by HPLC was challenging due to the labile nature of the N-diethoxymethyl group. Monitoring by NMR showed incomplete conversion (~ 15 mol% benzimidazole) as well as formation of a byproduct: N-ethylated benzimidazole (11). This byproduct resulted in formation of impurity 12 after the subsequent addition step. It was hypothesized that this impurity results from reaction of benzimidazole with ethyl benzenesulphonate, which itself formed under the reaction conditions.

Figure 3. Intermediate 10, byproduct 11 and impurity 12. The reaction conversion was increased to > 99 % by switching from toluene to triethylorthoformate as solvent. Formation of the alkylated impurity was suppressed by employing concentrated hydrochloric acid as the catalyst. The optimized conditions involved heating a mixture of benzimidazole (5) in 275 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.

triethylorthoformate with 2 mol % conc. HCl to 120 °C, combined with a partial solvent removal. Reactions under pure reflux resulted in higher levels of the impurity 12 (10-15 LCAP), due to formation and reaction of ethyl chloride. The acidic catalyst was quenched by diisopropylamine prior to use in the subsequent reaction step. Under these conditions conversions of > 97% were obtained without formation of alkylated impurities.


Selection of Reagent for Deprotection A screen of bases identified lithium diisopropylamide (LDA) as a preferred base for the subsequent deprotonation of 10. Lithium hexamethyldisilazide (LHMDS) led to incomplete conversions, while n-butyl lithium resulted in formation of impurities. Importantly, using the nitrile 9 as the electrophile allowed the reaction to be performed at – 25 °C, as compared to the corresponding reaction with ethyl ester 4, which required – 78 °C for good results. The reaction was performed by in-situ deprotonation of 10, in the presence of 9. Reaction monitoring with React-IR demonstrated that the reaction is very fast and that complete formation of imine 13 (R = Li, Figure 4) is achieved at the end of the base addition.

Figure 4. Intermediate 13, and impurity 14.

The subsequent imine hydrolysis and isolation appeared slightly more challenging. A direct quench of the reaction mixture with acetic acid resulted in a thick slurry which made efficient stirring difficult. Furthermore, the formation of a 1,2-Wittig-rearrangement product 14 was seen as an impurity under these quench conditions when an excess of LDA had been employed in the previous reaction step. The most effective quench protocol was identified as an inverse quench of the lithium imide into a mixture of aqueous 5N HCl in isopropanol, maintaining a temperature of below -5 °C. Direct crystallization of the hydrolyzed product occurred, and the material was isolated by simple filtration. Under these conditions the product was obtained in good yield (83-84%) and high purity (98.7 -99.5 HPLC area %). Safety evaluation of this reaction sequence did not identify any signs for concern and all isolated solids were stable by DSC analysis. The benzimidazole protection step, which was conducted in a batch mode, did not display any exothermic events by ARC examination. The safety of the nucleophilic addition was ensured by the dose-controlled reaction. Under these conditions no accumulation of potentially reactive intermediates was evidenced by React-IR. 276 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


The original conditions for the deprotection of the PMB-group called for using trifluoroacetic acid in dichloromethane. We sought to replace these conditions by a more environmentally benign reagent and solvent combination. A screen of acidic media identified sulfuric acid in acetic acid as a suitable deprotection system. Alternative sulfonic acids (methane, toluene and benzene sulfonic acids) afforded similar conversions, but resulted in biphasic reaction mixtures. Use of acetonitrile, toluene, anisole or 2-MeTHF as solvents led to either decreased conversions or to less clean reaction profiles as compared to acetic acid. Anisole was introduced as PMB-scavenger to avoid formation of oligomeric and polymeric byproducts, which caused issues with product isolation. Due to the low solubility of the target compound 1 in organic solvents, an extractive workup appeared impractical and therefore a direct isolation of the sulfate salt of 1 out of the reaction mixture was pursued. This material could be isolated directly in high yield (91-93 %) by simple filtration of the reaction mixture. The filter cake was washed with toluene in order to remove anisole and alkylated anisole derivatives. The safety of this deprotection step was evaluated via an RC-1 calorimetry study to demonstrate that anisole was effective at preventing any exothermic PMB-polymerizations (Figure 5). In this experiment sulfuric acid was added over 15 min, and the heat of reaction was measured as 85 kJ/mol, thus leading to an adiabatic temperature rise of 10 °C. The heat of reaction was deemed to be easily controllable using standard equipment, assuming an addition controlled dosing of sulfuric acid.

Figure 5. RC-1 trace for deprotection reaction of 6 to form 1. The salt break was performed by suspending the sulfate salt in water and adjusting the pH with two equivalents of sodium hydroxide. The free base formation step was a slurry to slurry transformation, but it performed robustly, and the entrainment of inorganic salts in the free base was minimal. Under these 277 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.

conditions free base 1 was isolated in quantitative yield and high purity (99.8 HPLC area %, 98.3 wgt %). The reaction sequence described was successfully scaled up to obtain 15 kilogram of the target compound 1.


Final Route and Process Safety Assessment With an enabling route to ketobenzimidazole 1 in hand to supply immediate needs, we shifted the project focus to develop a long-term route to this compound. Explorations into alternative disconnections did not reveal a superior route (Scheme 3). We therefore focused on reversing the order of reaction steps with the goal of eliminating the use of the protecting group PMB completely. This would remove the need for two steps, reduce costs of starting materials and improve the safety profile by no longer having the issue of PMB stability as a concern. Towards this end, we envisioned coupling 4-fluorobenzonitrile (8) directly with protected benzimidazole 10 followed by hydrolysis of the arylfluoride to afford the desired product 1 (Scheme 4). We employed the optimized conditions from the second generation synthesis for the first step to access intermediate 15. As described earlier, a direct acidic quench of the reaction mixture again resulted in a thick slurry, which led us to use the same inverse quench protocol already in place. The procedure afforded intermediate 15 in 82% yield and 99.7–100 HPLC area %.

Scheme 3. Alternative approaches towards core structure.



Scheme 4. Third generation synthesis of 1. Evaluation of the requisite hydrolysis reaction was initiated using 4 equivalents of KOH in a 1:1 mixture of DMSO/water; however, the reaction stalled at 90% conversion even upon prolonged heating at 100 °C (Scheme 4) (11). Aside from the incomplete conversion, we were particularly concerned about a recent report of a highly exothermic event occurring due to the decomposition of DMSO in the presence of fluoride ion (12). Because of this issue a base and solvent screen in both the presence and absence of water was conducted at elevated temperatures in an effort to find safe and scalable reaction conditions. No conversion was observed in either THF or CH3CN. Low conversions occurred in both sulfolane and water, and use of NMP resulted in decomposition. When either DMF or DMAc was employed, 100% conversion to the undesired aminated product 16 resulted (Figure 6). We determined that it was the product of fluoride displacement by dimethyl amine, which was liberated by basic hydrolysis of those solvents. Of all solvents screened, only DMSO afforded acceptable results. Both KOH and NaOH afforded superior results to those using LiOH in various solvents. The optimal conditions were determined to be aqueous 15N KOH (essentially saturated) in DMSO at 100 °C. Under these conditions 99.7% conversion was achieved. Because we were using KOH dissolved in hot DMSO, we ran an ARC study to determine its safety profile (Figure 7).

Figure 6. Undesired dimethylamine addition side-product 16 Our results show that at 100 °C the reaction proceeds slowly and it is not until 141 °C that an exotherm occurs. The highly exothermic decomposition of DMSO had a much higher onset temperature of 161 °C. Decomposition reactions, just like desired primary reactions, typically exhibit a rate increase with increasing 279 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


temperature eventually reaching its maximum rate. The “time to maximum rate” is an important number when dealing with process safety, and is simply the time it takes the reaction mixture, from a given temperature, to reach its maximum self-heating rate. It is a temperature-dependent quantity, and can be plotted directly from the ARC data (Figure 8). The data are usually corrected for the fact that the generated heat causes a temperature rise in both the sample cell as well as the sample itself. When a log scale is used for the time to maximum rate, the result is typically a straight line which can be extrapolated to longer times if desired. The temperature at which the time to maximum rate is 24 h is defined as the TD24, and this is considered a threshold temperature up to which point the thermal stability of the reaction mixture does not pose a serious problem (13). In this case the TD24 was determined to be 148 °C as shown by the extrapolation in Figure 8. When evaluating the safety of a process, one needs to consider the adiabatic temperature rise of the desired reaction and whether a cooling failure could lead to triggering the undesired decomposition. ARC experiments showed an adiabatic temperature rise of 6 °C for the hydrolysis. A cooling failure at the desired reaction temperature of 100 °C would only give a maximum temperature of 106 °C, which is well below the measured decomposition onset of 161 °C and also well below the TD24 of 148 °C, offering a wide margin of safety. This placed the process in criticality class 2 in the system proposed by F. Stoessel (11), which rates the safety of a process on a scale of 1 to 5 based on the relative positions of the process temperature, the maximum attainable temperature of the synthesis reaction, the TD24, and the boiling point of the solvent. The lower the criticality class, the more inherently safer the process is.

Figure 7. ARC-trace of hydrolysis reaction in DMSO.



Figure 8. Plot of temperature vs. time to maximum rate and extrapolation to 24 h.

After all safety investigations and process optimization, our process was conducted as follows. The reaction was performed on 50 g scale by charging 15N KOH to a solution of ketobenzimidazole 15 in DMSO and heating the mixture to 100 °C for ca. 16 h. The mixture was cooled to 75 °C and polish filtered to remove any suspended KF. The mixture was then diluted with water and the pH was adjusted to 4 at 50 °C using 5N HCl. Additional water was added and the product was isolated by filtration after cooling to ambient temperature. Using these conditions the product was obtained (48 g) in excellent yield (97%) and adequate purity (96.8 HPLC area %).

Conclusions Route selection and development efforts towards a key intermediate were driven by thorough safety evaluations and considerations of how to craft a safe process. In early aspects of the project, safety testing was leveraged to demonstrate absence of significant safety hazards in a fit-for-purpose delivery. Intermediate route improvements were supported by safety evaluations prior to execution of kilogram scale. Later route selection led to the discovery of a very short and efficient route (2 vs. 3 steps), which showed an acceptable safety profile (Scheme 4) (14). 281 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.

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Asakawa, K.; Dannenberg, J. J.; Fitch, K. J.; Hall, S. S.; Kadowaki, C.; Karady, S.; Kii, S.; Maeda, K.; Marcune, B. F.; Mase, T.; Miller, R. A.; Reamer, R. A.; Tschaen, D. M. Tetrahedron Lett. 2005, 46, 5081–5084. The yields in this scheme are not corrected for potency and purity of the intermediates. Bretherick’s Handbook of Reactive Chemical Hazards, 7th ed.; Urben, P. G., Ed.; Elsevier: 2007; Entry 2957, p 1039. Harger, M. J. Chem. Soc., Perkin Trans. 1 1997, 4, 527–532. Brewer, S. E.; Vickery, T. P.; Bachert, D. C.; Brands, K. M. J.; Emerson, K. M.; Goodyear, A.; Kumke, K. J.; Lam, T.; Scott, J. P. Org. Process Res. Dev. 2005, 9, 1009–1012. The sample of PMB-Cl was obtained from a vendor. The liquid supernatant was sampled and the ARC-test was performed without stirring. The ARC trace was recorded using the following conditions: heat-wait-seek from 30150 °C using 5 °C steps, wait time of 15 min, and exotherm threshold of 0.02 °C/min. Samples of PMB-Cl stabilized with potassium carbonate from a different vendor was also sampled and tested. The temperature onsets were found as low as 66 °C. ARC conditions: heat-wait-seek from 30-150 °C using 5 °C steps, wait time of 15 min, and exotherm threshold of 0.02 °C/min. Heterogeneous samples were stirred at 240 rpm. The pressure reading for the different samples was recorded, but cannot be used reliably since the formation of a polymeric foam led to partial blocking of the pressure sensor in some experiments. The sample of PMB-Cl stabilized with amylene was obtained from a vendor. The ARC-test was performed without stirring. The ARC trace was recorded using the following conditions: heat-wait-seek from 30-150 °C using 5 °C steps, wait time of 15 min, and exotherm threshold of 0.02 °C/min. Pickard, P. L.; Tolbert, T. L. J. Org. Chem. 1961, 26, 4886–4888. Alvernhe, G.; Laurent, A. Tetrahedron Lett. 1973, 13, 1057–1060. Yu, Z; Fossum, E.; Wang, D. H.; Tan, L-S. Synth. Commun. 2008, 38, 419–427. Wang, Z.; Richter, S. M.; Gates, B. D.; Grieme, T. A. Org. Process Res. Dev. 2012, 16, 1994–2000. Stoessel, F. Thermal Safety of Chemical Processes: Risk Assessment and Process Design, Wiley-VCH; Weinheim: 2008. The final route was not performed beyond 50 g scale and an even more thorough safety analysis (RC-1) would have to be performed prior to scale-up to kilogram scale.


Addressing Process Safety Hazards: Replacement of para

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