Control Strategy for the Manufacture of Brivanib Alaninate, a Novel

Article pubs.acs.org/OPRD

Control Strategy for the Manufacture of Brivanib Alaninate, a Novel Pyrrolotriazine VEGFR/FGFR Inhibitor Paul C. Lobben,* Evan Barlow, James S. Bergum, Alan Braem, Shih-Ying Chang, Frank Gibson, Nathaniel Kopp, Chiajen Lai, Thomas L. LaPorte, David K. Leahy, Jale Müslehiddinoğlu, Fernando Quiroz, Dimitri Skliar, Lori Spangler, Sushil Srivastava, Daniel Wasser, John Wasylyk, Robert Wethman, and Zhongmin Xu Chemical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States S Supporting Information *

ABSTRACT: This manuscript describes the control strategy for the commercial process to manufacture brivanib alaninate. The active pharmaceutical ingredient is a prodrug which is susceptible to hydrolysis. In addition to controlling hydrolysis, a robust strategy was required in order to control input and process-related impurities. Three significant aspects of control include understanding of the reaction parameters in order to minimize the regioisomer during the alkylation with (R)-propylene oxide, development of a design space through statistical models to control impurity formation, and the use of in situ FT-IR to monitor the hydrogenolysis of the Cbz protecting group.

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INTRODUCTION

Brivanib alaninate (1) is a new oncology therapy with potential applications against a wide variety of tumor types and several stages of disease progression.1,2 This alanine ester prodrug is orally active and a dual inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR-2) and fibroblast growth factor receptor (FGFR) tyrosine kinases, both of which modulate angiogenesis. Angiogenesis is characterized by the formation of a vascular network of blood vessels that serve growing tissue.3 The compound is expected to possess broadspectrum antitumor activity for use in the treatment of hepatocellular carcinoma, colorectal cancer, and fibroblast growth factor driven tumors. Brivanib alaninate, at a maximum daily dose of 800 mg, was evaluated in phase 3 clinical trials. The building blocks for the synthesis of brivanib alaninate were obtained from simple starting materials and our previously disclosed “quality gatekeeper” intermediate 3 (Scheme 1).4 The overarching development goal was to assemble these building blocks in a safe, robust, and efficient manner with optimum control over the critical quality attributes (CQAs) of the drug substance. The CQAs included identity, assay/potency, impurities (including stereoisomers), residual solvents, and particle size. (R)-Propylene oxide (RPO) and Cbz-L-alanine were used to install the side chain and the alanine prodrug moiety, respectively.5 The Cbz protecting group was chosen such that it could be removed under mild and neutral conditions in order to minimize hydrolysis of the ester. We expected that these two chemical processes would require indepth understanding of the process parameters as a means to control process-related impurities and develop a robust manufacturing process. The following discussion details the development challenges and the aspects of the control strategy required to meet the CQA of the drug substance and ensure consistent process performance and product quality. © XXXX American Chemical Society

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• Alkylation with RPO to incorporate the stereocenter of the parent drug 2 and maximize regioselectivity. • Development of a neutral and mild process that removes the carbobenzyloxy (Cbz) protecting group while minimizing hydrolysis of the resulting prodrug. • Application of PAT for the hydrogenolysis to allow realtime control and ensure product quality and improve process robustness.

RESULT AND DISCUSSION

The last two steps to manufacture brivanib alaninate include two consecutive telescoped sequences, each composed of two chemical reactions. The first requires saponification of the pivalate protecting group of 3 with an alkoxide base (Scheme 1). Without isolation, the resulting hydroxypyrrole 6 is then alkylated with (R)-propylene oxide. The resulting parent drug 2 (brivanib) directly crystallizes (direct-drop) from the reaction mixture. A subsequent recrystallization from acetone and water is required to further minimize process-related impurities, including residual (R)-propylene oxide.6 Installation of the prodrug begins with the acylation of the secondary alcohol with carbobenzyloxy-L-alanine (Cbz-L-ala). The unisolated intermediate7 is telescoped directly into the hydrogenolysis, using Pd/C and hydrogen in THF. After a distillation to effect a solvent exchange to ethyl acetate (EtOAc), the active pharmaceutical ingredient (API) is crystallized with the addition of heptanes in an overall yield of 61% with 99% purity. Special Issue: Application of ICH Q11 Principles to Process Development Received: April 15, 2014

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Scheme 1. Proposed Commercial Route for the Synthesis of Brivanib Alaninate (1)

Figure 1. Key impurities resulting from alkylation with (R)-propylene oxide.

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PROCESS DEVELOPMENT Penultimate Step: Deprotection and Alkylation. The penultimate process required 1 equiv of NaOMe8 for complete deprotection of the pivalate ester 3. Excess reagent afforded methanolysis of the product via ipso substitution at the indolearyl ether functionality. A wide variety of solvents were identified to be compatible with the deprotection reaction. We realized that the choice of solvent would play a critical role in both the overall efficiency of the process and resulting product quality. Ultimately, acetonitrile (CH3CN) was chosen based on an acceptable rate of conversion and a favorable impurity profile, vide inf ra. An added benefit of using CH3CN was that the intermediate sodium salt could be telescoped directly into the alkylation. If isolated as solid or stored as a solution, the salt of intermediate 6 slowly degraded. Although the degradants, mainly methanolysis/hydrolysis byproducts, were easily purged in the crystallization, an impact on yield was observed, and therefore, it was valuable to minimize these side reactions. Attention then focused on the development of the alkylation reaction, and specifically the control of the process-related impurities. Two impurities that required strict control were the regioisomer 4, which results from alkylation at the central carbon of (R)-propylene oxide and alkylation of the product at the indole-nitrogen to afford impurity 5 (Figure 1). The latter impurity was difficult to reject in the crystallization and subsequent recrystallization. The regioisomer impurity 4 ranges between 5 and 10% prior to crystallization, and it effectively purges in the crystallization. In addition it has a high tolerance in the downstream processing.9 Intermediate hydroxypyrrole 6 was controlled through optimization of process parameters, vide inf ra. In neat acetonitrile, 50% conversion with 20% byproducts occurred. Conversely, the use of water as the primary solvent provided complete conversion, albeit at the expense of poor regioselectivity. 67−80% water in acetonitrile afforded complete conversion, an acceptable impurity profile, and allowed for the direct crystallization of the parent drug 2 (Figure 2). While a lower ratio of water increased the regioselectivity, it also significantly slowed the reaction rate, thereby increasing the amount of methanolysis and hydrolysis byproducts. Further

Figure 2. Impact of the solvent ratio on regioselectivity and conversion.

optimization of the alkylation was realized through a design of experiments (DoEs). A recrystallization step from acetone/ water was required for additional control of impurities 4 and 6 and RPO. Control Strategy: (R) Propylene Oxide Alkylation. Once the optimal solvent ratio of 2:1 v/v water-to-acetonitrile was established, a design of experiments (DoE) protocol was implemented to delineate the impact of the key parameters on the impurity profile. The advantage of a DoE as compared to an empirical univariate approach is the ability to efficiently define the interactions between parameters. Results from the DoE indicated that the equivalents of (R)-propylene oxide, water/ acetonitrile ratio, and batch temperature required tight control in order to deliver product of a consistent quality. The alkylation of the salt of hydroxypyrrole 6 is a relatively slow reaction reaching completion in 12−60 h at 20−40 °C. The reaction time is particularly sensitive to temperature. For example a difference of three degrees in the batch temperature impacts the reaction time by up to 5 h. Although temperature increases the rate of the reaction, this parameter was also observed to increase side reactions and impurities.10 The two key impurities were generally found to be orthogonally formed at different points in the design space, but both increased at elevated temperatures. The worst conditions for the Nalkylation impurity 5 were found to be low water/acetonitrile B

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Figure 3. 95% Prediction intervals for the model-predicted design space impurities 4 (a, left) and 5 (b, right). The color axis to the right of the graph represents the levels of impurity.

constraints were considered in order to maximize the process robustness: • Align ranges with the capabilities of manufacturing equipment • ±10% variation on (R)-propylene oxide charge • ±5 °C temperature operating window. Five pilot plants batches at 100 kg scale and 11 laboratory experiments on 20 g scale were completed in order to verify the predicted results. The results agreed with the predicted values. The final design space for the alkylation is as follows: equivalents of (R)-propylene oxide of 4.4−5.5, internal batch temperature of 21−31 °C, and a ratio of water to acetonitrile of 1.8−2.3:1. Final Step: Acylation with Cbz-L-alanine. With a robust process for the synthesis of parent drug 2 developed, attention focused on the acylation of the chiral secondary alcohol with Cbz-L-alanine to produce the noncrystalline intermediate 7 (Figure 5). Although several protecting groups for the primary amine were considered, the carbobenzyloxy (Cbz) group was preferred for the ability to remove the protecting group under neutral conditions, and its commercial availability as a starting material. The final step can be divided into four processes: (1) the acylation with Cbz-L-alanine, (2) hydrogenolysis to remove the protecting group, (3) crystallization of the API, and (4) wet-milling to afford the specified particle size. In consideration of the impact that unit operations can have on the CQAs of a drug substance, including purity and particle size, the development of each step will be examined separately. A wide range of commercially available reagents and conditions used to activate the carboxylic acid toward esterification with 2 was evaluated. Activation of a carboxylic acid via the acid chloride was not practical due to epimerization of the chiral center. The resulting diastereomer from epimerization of Cbz-L-alanine was not purged in the crystallization, and thus, its formation had to be controlled. 1(3-(Dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC-HCl) as the acylating reagent proved to be robust with minimal epimerization and facile work-up. Acetone, THF, EtOAc, and CH3CN each offered >90% conversion after only 5 h, with a de greater than 95%. A solvent screen revealed that the rate of conversion was diminished in highly polar aprotic solvents; NMP and DMF afforded only 70% conversion with 95% de after 10 h at ambient temperature. THF was the preferred solvent due to an increase in the solubility of parent drug 2 and the ability to telescope directly into the hydrogenolysis process without a solvent exchange.

ratio and high equivalents of (R)-propylene oxide. Conversely, the worst conditions for regioisomer 4 were found to be high ratio water/acetonitrile and low equivalents of propylene oxide. A tight but workable range for each of the three parameters was defined. The next step was to understand the purgability of the key impurities in downstream processing to define a robust multivariate design space. Spiking studies determined that the API process could tolerate up to 1.9% of the regioisomer impurity 4 and 0.34% of the N-alkylation impurity 5. Accordingly, based on the process capability for purging each impurity, the alkylation design space was established such that a maximum of 5.9% of the regioisomer impurity 4 and a limit of 0.34% for 5 would be present in the first-drop direct crystallization of parent drug 2 prior to the required recrystallization step. Impurity 5 does not purge in the crystallization or recrystallization.11 The regioisomer 4 purges roughly by 50% in the first-drop crystallization, affording an internal acceptance criteria [upper limit] of ≤5.9%. A further 67% reduction was observed in the recrystallization step to achieve the tolerance of 1.9%. To increase the understanding of the multivariate interactions and guide the design space development, a statistical model was developed to predict the level of the two critical impurities across the range of parameters.6 The data collected from laboratory experiments and pilot plant batches was used to develop a multivariate regression for each impurity as a function of the three key process parameters. These equations were further refined to evaluate the upper 95% prediction intervals of the model in order to establish the edge of failure. The equations for the 95% prediction interval were obtained by fitting the estimates provided by SAS software for each of the calibration data points used to generate the model.12 Using these equations as guides to define the design space provided a conservative set of reaction conditions to ensure quality. Figure 3 shows the multidimensional graphs generated from the statistical models. The left graph highlights the range of 4 (4.3−5.9 area %) observed when operating within the design space. The right graph similarly displays the level of impurity 5 within the design space, ranging from 0.17 to 0.34 area %. The design space is quite sensitive to the specification limit of 1.9% for 4 previously described for the parent drug 2. For example, tightening the limit of impurity 4 by 0.1% to 1.8% reduces the space by 33%. Finally, experimental verification for the proposed design space was focused on the regions predicted to form the highest impurity levels. In building this new design space, the following C

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Figure 4. Hydrogenolysis process-related impurities.

Figure 5. Implementation of FT-IR as part of the hydrogenolysis control strategy.

142 (BASF) afforded a balanced rate of reaction and a favorable impurity profile. As the API molecule possesses sensitive functional groups such as a primary amine, an ester, and a labile indole−aryl ether bond, the choice of solvent was limited to polar aprotic solvents.17 Both EtOAc and THF proved effective solvents for the hydrogenolysis. THF was selected because of improved catalyst dispersion of the water wet-catalyst and a resulting lower catalyst loading. Ethyl acetate has a liability of N-acylation of the primary amine catalyzed by the carbon dioxide byproduct.18 Control Strategy: Hydrogenolysis PAT. To develop a robust strategy, three robust in-line FT-IR methods were developed to monitor both the concentration of starting material 2 and the concentration of carbon dioxide byproduct in the reaction mixture.19 Full conversion was required due to poor purging of the intermediate 7 in the final crystallization. The reaction end point was set at >99.9% conversion by inline FT-IR due to the limitation of off-line HPLC. A fast reaction, that is, an overcharge of catalyst (or too long of a reaction), was to be avoided in order to minimize overreduction and to afford impurity 8. As with other in-process related impurities, the rate of formation of impurity 8 depends on the rate of the desired reaction. If the reaction was proceeding as expected, it was important to stop the hydrogenolysis when the end point was reached by immediately purging hydrogen and CO2. However, the FT-IR method20 was found not to be sensitive to less than 2.0 wt % of intermediate 7. As a result, a chemometric model using partial least-squares combined with the reaction kinetics to accurately predict the reaction end point. The chemometric model alone was not enough. Once the level of intermediate 7 reached 5%, rate data was collected until a level of 3% was reached. At this point, the rate constant was obtained and the time to reach 99.9% conversion was estimated based on the first order approximation.21 The initial reaction kinetics was used to enabled the detection of catalyst poisoning which may result in a slow reaction and eventual hydrolysis of the prodrug.22 Upon

However, DMF as a cosolvent was necessary, particularly at lower temperatures, in order to increase the solubility of the EDAC hydrochloride and the resulting urea byproduct.13 Due to the modest nucleophilicity of parent drug 2, DMAP was required to catalyze the acylation.14 However, Cbz-Lalanine was observed to racemize under reaction conditions, presumably due to the keto−enol tautomerization of the polarized acylpyridinium intermediate.15 Optimum control of the diastereomer impurity was realized by charging the Cbz-Lalanine last to the reaction mixture at 0 °C. The unisolated intermediate 7 (Figure 5) was stable to epimerization under reaction conditions even when subjected to prolonged reaction times. The Cbz-alanine byproducts and alanine-related oligomers were found to impact the efficiency of the final crystallization. Immediate quench of the reaction was required to minimize oligomerization of Cbz-ala. When telescoped through the hydrogenolysis, the resulting di-, tri-, and tetra-alanine oligomers negatively impacted the purging of impurity 8.16 Furthermore, an aqueous work-up removed additional Cbz-Lalanine-related byproducts. The work-up consisted of sequential aqueous acidic, basic, and neutral washes. Following the aqueous work-up and an azeotropic distillation to dry the solution, the THF solution of intermediate 7 was telescoped into the hydrogenolysis. The control strategy for the acylation of parent drug 2 focused on (1) low temperature at −5−5 °C, (2) charging the Cbz-L-alanine last, and (3) immediate quench of the reaction upon reaching the end point. Final Step: Hydrogenolysis. Hydrogenolysis of intermediate 7 proved to be complicated due to the lability of 1. Three chemical pathways required control: (1) formation of parent drug 2, (2) over-reduction to afford impurity 8, and (3) transamidation to afford dialanine impurity 9 and parent drug 2. Catalysts with high activity would typically afford nearly quantitative indole cleavage impurity 8 (Figure 4). A slow reaction routinely resulted in >5% hydrolysis of the prodrug 1 to form parent 2 as well as formation of the dialanine 9. ESCAT D

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pressure, catalyst loading, headspace, and kLa and at high values for concentration and water content (KF). A low hydrogen mass transfer condition will lead to slower reaction kinetics and the possibility of incomplete reaction and unacceptable impurity profile.25 These parameters afforded a reaction time of 9.5 h with an acceptable in-process impurity profile. All 12 experiments passed the minimum initial kinetic target of 50% conversion over 20 min and in-process impurity profile. None required a kicker charge of catalyst. The proven acceptable range (PAR) for each parameter is shown in Table 1.

reaction completion, over-reduction impurity 8 continues to form in the presence of the catalyst, while dissolved carbon dioxide catalyzes the hydrolysis of the product. Therefore, it was important to remove carbon dioxide and filter the catalyst immediately. During the purge of hydrogen, the FT-IR method also monitored the level of carbon dioxide to an end point of 600 ppm or less. This was then followed by filtration. The dissolved carbon dioxide catalyzes the hydrolysis of the prodrug at a rate of 2% per week at 50 °C. Seeds of 1 (250 g) were charged to the solution in order to induce nucleation. The resulting thin slurry was aged for 20 min prior to the charge of the second volume of heptanes (263.1 kg), also over 40 min at >50 °C. The resulting slurry was cooled to 20 °C over 2 h and aged overnight before recirculating through a wetmill to afford a D90 particle size of 51 μm. The slurry was isolated by filtration, and the mother liquor was displaced with 20% EtOAc in heptanes (206.2 kg), followed by two successive displacement washes with heptanes (272.6 kg). The cake was dried under full vacuum at 50 °C, which upon discharge afforded 53.4 kg (61% yield) of 1 as a white to off-white crystalline powder. Product losses of ∼15% were attributed to

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ASSOCIATED CONTENT

S Supporting Information *

A description of the procedures used to handle (R)-propylene oxide (RPO) during isolation and recrystallization; the statistical models that were generated for impurities 4 and 5 and the data visualization tools; a discussion of the design space for the manufacture of parent drug 2; and a discussion of the development of the PAT FT-IR methods used to monitor the hydrogenolysis of intermediate 7. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Phone: (732) 227.7191. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors greatly acknowledge the following individuals for their direct contribution to a successful technology transfer to manufacturing: Jose E. Tabora (modeling), Michael Hrystak (PAT), and San Kiang (early FT-IR method). Additional appreciation is given to Michael Randazzo and Jaan Pesti for careful reading of the drafts of the manuscript.

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REFERENCES

(1) (a) Crispino, G. A.; Hamedi, M.; Laporte, T. L.; Thornton, J. E.; Pesti, J. A.; Xu, Z.; Lobben, P. C.; Leahy, D. K.; Muslehiddinoglu, J.; Lai, C.; Spangler, L. A.; Discordia, R. P. Process for the Preparation of [(1R), 2S]-2-Aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester. PCT Int. Appl. WO/2007/124332. (b) Cai, Z.-w.; Zhang, Y.; Borzilleri, R. M.; Qian, L.; Barbosa, S.; Wei, D.; Zheng, X.; Wu, L.; Fan, J.; Wautlet, B. S.; Mortillo, S.; Jeyaseelan, R.; Kukral, D. W.; Kamath, A.; Marathe, P.; D’Arienzo, C.; Derbin, G.; Barrish, J. C.; Robl, J. A.; Hunt, J. T.; Lombardo, L. J.; Fargnoli, J.; Bhide, R. S. J. Med. Chem. 2008, 51, 1976−1980. (c) Bhide, R. S.; Cai, Z.-W.; Zhang, Y.-Z.; Qian, L.; Wei, D.; Barbosa, S.; Lombardo, L. J.; Borzilleri, R. M.; Zheng, X.; Wu, L. I.; Barrish, J. C.; Kim, S.-H.; Leavitt, K.; Mathur, A.; Leith, L.; Chao, S.; Wautlet, B.; Mortillo, S.; Jeyaseelan, R.; Kukral, D.; Hunt, J. T.; Kamath, A.; Fura, A.; Vyas, V.; Marathe, P.; D’Arienzo, C.; Derbin, G.; Fargnoli, J. J. Med. Chem. 2006, 49, 2143−2146. (d) Borzilleri, R. M.; Zheng, X.; Qian, L.; Ellis, C.; Cai, Z.-w.; Wautlet, B. S.; Mortillo, S.; Jeyaseelan, R.; Kukral, D. W.; Fura, A.; Kamath, A.; Vyas, V.; Tokarski, J. S.; Barrish, J. C.; Hunt, J. T.; Lombardo, L. J.; Fargnoli, J.; Bhide, R. S. J. Med. Chem. 2005, 48, 3991−4008. (e) Hunt, J. T.; Mitt, T.; Borzilleri, R.; Gullo-Brown, J.; Fargnoli, J.; Fink, B.; Han, W.-C.; Mortillo, S.; Vite, G.; Wautlet, B.; Wong, T.; Yu, C.; Zheng, X.; Bhide, R. J. Med. Chem. 2004, 47, 4054− 4059. (2) (a) Padilla, I.; Siu, L. L. Expert Opin. Invest. Drugs 2011, 20, 577− 586. (b) Ayers, M.; Fargnoli, J.; Lewin, A.; Wu, Q.; Platero, J. S. Cancer Res. 2007, 67, 6899−6906.

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into the crystallization, this mixture of byproducts was shown to negatively impact the tolerance of in-process related impurities during the final crystallization. (17) THF, isopropyl acetate, n-butyl acetate, 2-methyltetrahydrofuran, and ethyl acetate solvents were acceptable for the hydrogenolysis. Concern with acetone was Schiff-base formation, and alcohols had the possibility to hydrolyze the ester. Dichloromethane was discounted due to the risk of forming bridged methylene dimers with primary amines, (18) (a) Müslehiddinoğlu, J.; Lobben, P.; Leung, S.; Spangler, L.; Kiang, S. Catal. Today 2007, 123, 164−170. (b) For a somewhat related account detailing the impact of carbon dioxide on ruthenium catalyzed reductive amination, please see: Strotman, N. A.; Baxter, C. A.; Brands, K. M. J.; Cleator, E.; Kraska, S. W.; Reamer, R. A.; Wallace, D. J.; Wright, T. J. J. Am. Chem. Soc. 2011, 133, 8362−8371. (19) Stirred tank reactors under hydrogen pressure may need to be purged with nitrogen prior to sampling. PAT offers the benefit of not disturbing the gas composition until the end point. (20) Three distinct peaks for intermediate 7 were utilized. The most distinct peak due to a CO stretching band is unique for the input material, and is located at 1746−1670 cm−1, and the bending regions at 1216−1194 cm−1 and 1136−1109 cm−1. For carbon dioxide the asymmetric stretch for the molecule is easily distinguished as it appears at a higher wavenumber than the bending modes and at a lower wavenumber than the stretching modes of organic compounds. The peak appears as a singlet at 2339−1 not a doublet, indicating it is dissolved in solution. (21) By knowing the mass of intermediate 7 charged to the reaction vessel and accurately measuring the concentration by FT-IR, the proper catalyst loading was assured. FT-IR is used to develop a safe process and monitor sensitive reactions. For recent examples see: (a) Dunetz, J. R.; Berliner, M. A.; Xiang, Y.; Houck, T. L.; Salingue, F. H.; Chao, W.; Yuandong, C.; Shenghua, W.; Huang, Y.; Farrand, D.; Boucher, S. J.; Damon, D. B.; Makowski, T. W.; Barrila, M. T.; Chen, R.; Martinez, I. Org. Process Res. Dev. 2012, 16, 1635−1645. (b) Sosa, A. C. B.; Conway, R.; Williamson, R. T.; Suchy, J. P.; Edwards, W.; Cleary, T. Org. Process Res. Dev. 2011, 15, 1458−1463. (c) Pesti, J.; Chen, C.-K.; Spangler, L.; DelMonte, A. J.; Benoit, S.; Berglund, D.; Bien, J.; Brodfuehrer, P.; Chan, Y.; Corbett, E.; Costello, C.; DeMena, P.; Discordia, R. P.; Doubleday, W.; Gao, Z.; Gringras, S.; Grosso, J.; Haas, O.; Kacsur, D.; Lai, C.; Leung, S.; Miller, M.; Müslehiddinoğlu, J.; Nguyen, N.; Qiu, J.; Olzog, M.; Reiff, E.; Thoraval, D.; Totleben, M.; Vanyo, D.; Vemishetti, P.; Wasylak, J.; Wei, C. Org. Process Res. Dev. 2009, 13, 716−728. (22) The availability of 5 wt % kicker charge of catalyst was a contingency in case of an unplanned deviation in process parameter(s), including slow reaction kinetics recorded by FT-IR, which may result in hydrolysis of the prodrug. (23) For example, the rate of formation of over-reduction impurity 8 increased five times with a 10 °C increase in batch temperature. (24) On lab scale in EtOAc and with 10 area %. Sodium methoxide was chosen due to quality and cost considerations. (9) The moderate regioselectivity is likely due to polarity and/or Hbonding, slightly facilitating one transition state. However, screening 20 Lewis acids to soften the oxirane, according to Pearson’s hard−soft acid−base (HSAB) theory, eroded the regioselectivity in all cases. (a) Ho, T.-L. Chem. Rev. 1975, 75, 1−20. (b) Hanson, R. M. Chem. Rev. 1991, 91, 437−475. (c) Maheswara, M.; Subba, K.; Rao, V. K.; Do, J. Y. Tetrahedron Lett. 2008, 49, 1795−1800. (d) Halimehjan, A. Z.; Gholami, H.; Saidi, M. Green Chem. Lett. Rev. 2012, 5, 1−5. (10) An excess of (R)-propylene oxide was required due to the competing hydrolysis, as approximately 20% of the starting material is hydrolyzed to (R)-1,2-propanediol under the reaction conditions. (11) The N-alkylation impurity 5 was found to be relatively less soluble than the desired parent drug. A screen of crystallization solvents ranging from ethers, acetates, and hydrocarbon all failed to purge this impurity. A variety of absorption techniques, including carbon pads, also failed to reduce the level of this impurity. (12) The analysis was performed with SAS software (Statistical Analysis Systems, SAS Institute Inc., SAS/STAT(R) 9.2 User’s Guide, 2nd ed, 2009.). (13) The addition of DMF as a cosolvent was found to greatly enhance the rate of the reaction in THF and EtOAc by increasing the solubility of the EDAC and reducing precipitation of the urea byproducts. 5−15 vol % DMF gave enhanced reaction rates without dramatically compromising de; the use of 20% DMF does begin to erode the diastereoselectivity, and without DMF the reaction mixture is difficult to stir, especially at lower temperatures. (14) (a) Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron 1978, 34, 2069−2076. (b) Myers, A. G.; Glatthar, G.; Hammond, M.; Harrington, P. M.; Kuo, E. Y.; Liang, J.; Schaus, S. E.; Wu, Y.; Xiang, J.N. J. Am. Chem. Soc. 2002, 124, 5380−5401. (c) Kamijo, T.; Yamamoto, R.; Harada, H.; Iizuka, K. Chem. Pharm. Bull. 1983, 31, 3724. (d) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368−6380. (15) Inorganic and trialkylamine bases were completely ineffective. Pyridines substituted in the two-position were expected to induce A1,3 strain in keto−enol tautomerization, thus minimizing epimerization. In reality,