Process Safety in the Large-Scale Manufacture of an Adamantane α

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Chapter 6

Process Safety in the Large-Scale Manufacture of an Adamantane α-Ketoacid Precursor of Saxagliptin Joerg Deerberg* Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08901-1588 *E-mail: [email protected]

Development of a safe, metric-ton scale batch process for production of a 3-hydroxy-adamantane-1-α-oxoacetic acid, an intermediate in the manufacture of saxagliptin (Onglyza®), presented two key challenges for process safety: A Reformatsky reaction and a bridgehead hydroxylation of the adamantane core using nitric acid. Safety aspects were addressed through detailed examination of operating ranges and thermochemical and mechanism-based risk analysis and mitigation.

Introduction Saxagliptin 1 (Onglyza®) is a highly potent inhibitor of dipeptidyl peptidase IV (DPP4) for the treatment of Type II Diabetes Mellitus (1–6). The commercial process for manufacture of 1 (7) assembles the principal building block (S)-3-hydroxy-adamantylglycine 2 directly from its 3-hydroxy-adamantane-1-αoxo-acetic acid precursor 3 via enzymatic reductive amination (8, 9) (Scheme 1). We therefore sought a safe and cost-effective large-scale synthesis capable of producing metric-ton quantities of 3. Initial approaches starting from adaman-tane α-hydroxy- and α-oxo acetates 4 and 5 (8) identified bridgehead hydroxyl-ation at C3 of the adamantane core as the key challenge to a successful bulk synthesis of 3. Both 4 and 5 were unstable towards a wide range of oxidation conditions (1, 10–19), thus precluding their use on scale. For example, KMnO4 (1, 16–18) as oxidant led to extensive decarbonylation (20), producing a mixture of adamantane carboxylates, thus rendering isolation of pure 3 impractical.

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Scheme 1. Disconnective scheme for saxagliptin 1 and α-ketoacid precursor 3 The stability issue in the hydroxylation step was ultimately addressed by introduction of gem-dichloride substitution in the α-position of adamantylacetic acid, as in 6. Nitric acid (HNO3) stood out as the best-performing reagent for oxidation; despite the strongly acidic medium required (19), no decomposition of either substrate or product was detected under the reaction conditions. This discovery led to our eventual manufacturing route for 3 (21) (Scheme 2). Therein, Reformatsky reduction of methyl trichloroacetate (MTCA, 7) in the presence of zinc powder, followed by concomitant O-silylation (Step 1a) (22–24) yielded α,α-dichloroketene acetal 9 (KTA), which was subjected to Zn(II)-chloride mediated α-tert. alkylation (25, 26) with commercially available 1-bromo-adamantane 10. The resulting product 11 underwent smooth mono-oxidation of the bridgehead position with nitric acid in concentrated sulfuric acid as co-promoter and reaction medium, yielding 12. Ester hydrolysis provided free acid 13, which underwent smooth thermal saponification (27) of the α-chloro substituents in the presence of mild aqueous base (Na2HPO4) at elevated temperature (90 °C) to provide desired 3.

Scheme 2. Bulk manufacturing route for adamantane α-ketoacid 3 (21) With its attractive overall yields (60-62%, from 10), inexpensive commercial raw materials, and excellent stability of intermediates, the above route was of interest for use on a manufacturing scale. However, prior to any such application, critical questions regarding the inherent safety of two key transformations were to 170 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.

be addressed: Reformatsky reaction of 7 (Step 1a) and bridgehead hydroxylation of the adamantane core in 11 (Step 2).

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Reformatsky Reaction From the outset, we expected to address questions regarding exotherm control, as well as the activation and eventual safe removal of unreacted zinc powder. In addition, we needed assurances that any reagent accumulation could be detected at an early stage and that effective engineering controls could be implemented to control the exotherm and allow safe stoppage of the reaction at any moment, independent of the degree of conversion and the condition of the batch. To achieve such an inherently safer design (28), our goal was to identify appropriate layers of protection throughout the process to minimize any residual risks towards safe execution. Each finalized process was to be evaluated by a what-if analysis to ensure core risks and corrective actions were fully defined prior to implementation on scale.

Process Design and Thermochemical Evaluation As the first safety feature, we adapted Imashiro’s protocol (23), wherein the two liquid reagents – methyl trichloroacetate (MTCA, 7, limiting reagent) and chlorotrimethylsilane (8, 1.05 equiv) – were added jointly as a homogeneous solvent-less solution from the same reservoir to a suspension of zinc dust (1.5 equiv) in tetrahydrofuran (THF) (Scheme 3). This charge protocol enabled immediate stoppage of reagent flow in the event of issues with reaction initiation or excessive heat generation. A kill switch to the transfer pump allowed for immediate interruption of the reagent addition, should such a need arise. To eliminate the risk of accidental uncontrolled reagent flow, charges were to be made above-surface via pump transfer from a reservoir physically located at a level below the main reactor in which the Reformatsky reaction was to take place.

Scheme 3. Reformatsky reaction by co-addition of reagents to zinc slurry (23) We further studied reaction initiation in the laboratory using a broad range of commercial types of zinc powder. Common procedures for metal surface activation, such as pre-addition of 1,2-dibromoethane (29, 30) or washing of the Zn powder with acid prior to use (31), were inadequate in our hands, leading to unreliable initiation patterns and delayed exotherms. Alternate non-chemical 171 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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activation protocols, such as sonication (32, 33), were deemed impractical on scale. Among the various types of Zn tested, our screen showed that small particle size ( 4.0. When the wash pH passed specification, the organic extracts were concentrated under slight vacuum below 40 °C to approx. 650–750 L of total volume. The rich concentrate containing 12 (264.1 kg; 0.90 kmol; 98% yield) was directly introduced into the next step (ester hydrolysis). 182 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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Adamantane Hydroxylation: What-If Analysis In the final process, key design features, such as exotherm control, the absence of incompatible solvents, and avoidance of nitrous gases have been incorporated. With stability risks absent under normal processing conditions, attention was focused on potential parameter excursions and failure paths (Table 5). If the reagent charge cannot be completed (e.g., pump failure, cooling failure, power failure, poorly controlled exotherm, etc.), the batch remains in a stable state, even if no further actions are taken. Irrespective of the degree of conversion, and in the event of an accidental overcharge of nitric acid, the reaction mass remains stable and can at any point be quenched into an excess of aqueous sulfamic acid solution, thus eliminating all oxidative species or gases. While nitrous gases are not formed in the process, as an additional layer of protection, the equipment headspace was continually purged with nitrogen and exhaust lines directed to a scrubber containing dilute aqueous sulfamic acid.

Conclusions Manufacture of saxagliptin precursor 3-hydroxy-adamantane-1-α-oxo-acetic acid (3) was enabled through a 4-step synthesis starting from inexpensive 1-bromoadamantane. The present contribution describes examination of two critical process steps for risk factors with potential impact on operational safety: Reformatsky reduction of methyl trichloroacetate (MTCA) using elemental zinc and selective bridgehead hydroxylation of the adamantane core with nitric acid. Safety aspects were evaluated through detailed thermochemical and mechanism-based risk analysis. Risk mitigation was achieved through a self-limiting design, incorporating effective engineering controls that ensure stable batch processing under a variety of planned and unplanned operating conditions, including partial and complete system outages. Key design features are controlled pump charges of reagents from reservoirs located below the main reactors, preventing accidental siphoning, and the ability to safely proceed to work-up at any time during the process, irrespective of the degree of conversion or reagent over-/undercharges. Potential failure paths were identified and mitigated through what-if analyses. The resulting processes were successfully applied to the commercial manufacture of 3-hydroxy-adamantane-1-α-oxo-acetic acid (3) on a metric-ton scale.

Acknowledgments The author would like to thank the following present and former colleagues for their contributions to this work: Dr. Jollie Godfrey, Rita Fox (route discovery), Dr. Zhinong Gao, Dr. Jurong Yu, Jason Zhu (route development), Carlos Escobar, Dr. Francis J. Okuniewicz, Dr. Simon Leung, Dr. Srinivas Tummala, Dr. Jale Müslehiddinoğlu, and Dr. Steven H. Chan (thermochemical analyses). 183 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.

References 1.

2. 3. Downloaded by UNIV OF HOUSTON MAIN on November 26, 2014 | http://pubs.acs.org Publication Date (Web): November 20, 2014 | doi: 10.1021/bk-2014-1181.ch006

4.

5. 6. 7. 8.

9.

10. 11.

12. 13. 14. 15. 16. 17. 18. 19.

Augeri, D. J.; Robl, J. A.; Betebenner, D. A.; Magnin, D.; Khanna, A.; Robertson, J. G.; Wang, A.; Simpkins, L. M.; Taunk, P.; Huang, Q.; Han, S.P.; Abboa-Offei, B.; Cap, M.; Xin, L.; Tao, L.; Tozzo, E.; Welzel, G. E.; Egan, D. M.; Marcinkeviciene, J.; Chang, S. Y.; Biller, S. A.; Kirby, M. S.; Parker, R. A.; Hamann, L. G. J. Med. Chem. 2005, 48, 5025–5037. Tahrani, A. A.; Piya, M. K.; Barnett, A. H. Adv. Ther. 2009, 26, 249–262. Neumiller, J. J.; Campbell, R. K. Am. J. Health Syst. Pharm. 2010, 67 (18), 1515–1525. Kulkarni, V. S.; Senthil Kumar, G. P.; Lele, M. D.; Gaikwad, D. T.; Patil, M. D.; Gavitre, B. B.; Bobe, K. R. Int. J. Pharm. Sci. Rev. Res. 2011, 6, 147–151. Barnett, A. H.; Charbonnel, B.; Li, J.; Donovan, M.; Fleming, D.; Iqbal, N. Clin. Drug Invest. 2013, 33 (10), 707–717. Karyekar, C. S.; Frederich, R.; Ravichandran, S. Int. J. Clin. Pract.e 2013, 67, 759–767. Savage, S. A.; Jones, G. S.; Kolotuchin, S.; Ramrattan, S. A.; Vu, T. C.; Waltermire, R. E. Org. Proc. Res. Dev. 2009, 13, 1169–1176. Politino, M.; Cadin, M. M.; Skonezny, P. M.; Chen, J. G. Process for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor. Bristol-Myers Squibb Co., WO 2005/106011, Nov. 10, 2005. Hanson, R. L.; Goldberg, S. L.; Brzozowski, D. B.; Tully, T. P.; Cazzulino, D.; Parker, W. L.; Lyngberg, O. K.; Vu, T. C.; Wong, M. K.; Patel, R. N. Adv. Synth. Catal. 2007, 349, 1369–1378. Adamantane C3-hydroxylation using bromine or NBS: Vodička, L.; Janku, J.; Burkhard, J. Coll. Czech. Chem. Commun. 1983, 48, 1162–1172. Manchand, P. S.; Cerruti, R. L.; Martin, J. A.; Hill, C. H.; Merrett, J. H.; Keech, E.; Belshe, R. B.; Connel, E. V.; Sim, I. S. J. Med. Chem. 1990, 33, 1992–1995. Using CrO3: Drivas, I.; Mison, P. Bull. Soc. Chim. Fr. 1984 (Pt. 2), 252–264. Kovalev, V. V.; Shokova, E. A.; Knyazeva, I. V. Zh. Org. Khim. 1986, 22, 776–780. Using DDQ/acid: Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Horaguchi, T. J. Chem. Soc., Perkin Trans. 1 2001, 3230–3231. Using CAN/h·v: Baciocchi, E.; Del Giacco, T.; Sebastian, G. V. Tetrahedron Lett. 1987, 28, 1941–1944. Using KMnO4: Moiseev, I. K.; Klimochkin, Yu. N.; Zemtsova, M. N.; Trakhtenberg, P. L. Zh. Org. Khim. 1984, 20, 1435–1438. Anderson, G. L.; Burks, W. A.; Harruna, I. I. Synth. Commun. 1988, 18, 1967–74. Li, J.; Zhang, S.; Zhou, H.; Peng, J.; Feng, Y.; Hu, X. Lett. Org. Chem. 2012, 9, 347–350. Using HNO3/H2SO4: Lednicer, D.; Heyd, W. E.; Emmert, D. E.; TenBrink, R. E.; Schurr, P. E.; Day, C. E. J. Med. Chem. 1979, 22, 69–77. 184 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.

Downloaded by UNIV OF HOUSTON MAIN on November 26, 2014 | http://pubs.acs.org Publication Date (Web): November 20, 2014 | doi: 10.1021/bk-2014-1181.ch006

20. Permanganate oxidation of 4, 5, or, alternatively, of commercial 1-acetyl-adamantane yielded large proportions of 3-hydoxy-adaman-tane-1carboxylic acid from decarbonylation of co-formed desired product 3. 21. Godfrey, J. D., Jr.; Fox, R. T.; Buono, F. G.; Gougoutas, J. Z.; Malley, M. F. J. Org. Chem. 2006, 71, 8647–8650. 22. Braun, M.; Vonderhagen, A.; Waldmüller, D. Liebigs Ann. Chem. 1995, 1447–1450. 23. Imashiro, R.; Kuroda, T.; Ozaki, y.; Yamagishi, M.; Yamanaka, T. EP 0808824A2; 1997. 24. Imashiro, R.; Kuroda, T. Tetrahedron Lett. 2001, 42, 1313–1315. 25. Reetz, M. T.; Schwellnus, K. Tetrahedron Lett. 1978, 1455–1458. 26. Bott, K. Tetrahedron Lett. 1994, 35, 555–556. 27. A kinetic study on the saponification of α,α-dichloroacetic acid 12 to desired α-oxoacetic acid 3 showed that extrusion of chloride occurs via intermediacy of a-lactones, followed by hydrolytic ring opening with hydroxide ion attack at the α-carbon (c.f.: Ref. (21)). 28. Hendershot, D. C. Professional Safety 2011, 48–55. 29. Knochel, P.; Normant, J. F. Tetrahedron Lett. 1984, 25, 1475–1478. 30. Clark, J. D.; Weisenburger, G. A.; Anderson, D. K.; Colson, P.-J.; Edney, A. D.; Gallagher, D. J.; Kleine, H. P.; Knable, C. M.; Lantz, M. K.; Moore, C. M.; Murphy, J. B.; Rogers, T. E.; Ruminski, P. G.; Shah, A. S.; Storer, N.; Wise, B. E. Org. Proc. Res. Dev. 2004, 8, 51–61. 31. Newman, M. S.; Arens, F. J. J. Am. Chem. Soc. 1955, 77, 946–947. 32. Repič, O.; Vogt, S. Tetrahedron Lett. 1982, 23, 2729–2732. 33. Suslick, K. S.; Doktycz, S. J. J. Am. Chem. Soc. 1989, 111, 2342–2344. 34. α-Substituted O-silylketene acetals such as 9 suffer gradual Lewis-acid catalyzed migration of the silyl group to the α-carbon (c.f.: Emde, H.; Simchen, G. Liebigs Ann. Chem. 1983, 816–834. In the case of 9, a 7–9 h time window was available before rearrangement began to set in. Upon reaction completion, stabilization was achieved through addition of a hydrocarbon solvent (n-hexane or n-heptane), which halts rearrangement. 35. For the formation of Grignard reagents, the duration of the induction period has been correlated to the amount of moisture present in the system: Gilman, H.; Vanderwal, R. J. Recl. Trav. Chim. Pays-Bas. 1929, 48, 160–162. 36. Meyer, M.; Shimodaira, C. C. R. Hebd. Séances Acad. Sci. 1956, 243, 846–848. 37. Sprich, J.; Lewandos, G. S. Inorg. Chim Acta 1983, 76, L241–L242. 38. Hauser, C. R.; Breslow, D. S. Org. Synth. 1941, 21, 51. 39. Bieber, L. W.; Malvestiti, I.; Storch, E. C. J. Org. Chem. 1997, 62, 9061–9064. 40. For Grignard reagents, the induction period was reported to be due to gradual dissolution of a passivating oxide layer on the magnesium surface by the initially formed Grignard reagent itself. The bulk insertion reaction then engages once enough of the active metal below becomes available. Presence of water causes formation of insoluble by-products which blind the metal 185 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.

Downloaded by UNIV OF HOUSTON MAIN on November 26, 2014 | http://pubs.acs.org Publication Date (Web): November 20, 2014 | doi: 10.1021/bk-2014-1181.ch006

41.

42.

43.

44. 45. 46. 47.

48.

49. 50. 51. 52. 53.

54. 55.

surface, thus retarding onset of the insertion reaction: Tuulmets, A.; Kirss, M. Main Group Met. Chem. 1997, 20, 345–349. The term ‘batch temperature control mode’ refers to a computerized setpoint module for a jacketed reactor designed to maintain a constant internal vessel temperature. In response to any decrease/increase in batch temperature, rapid heating or cooling is applied through automated injection of a thermal transfer fluid circulating through the jacket. Operating in this mode allows visualization of heat flow through the reactor walls by charting the temperature difference between the reactor vessel and the jacket (Tr-Tj). This measure is proportional to heat flow as long as the automated temperature control mode remains engaged. To enable continuous monitoring of the reduction step with minimum response times, the inline IR spectrometer was inserted into a high-capacity pump-around loop capable of turning over the reactor contents within 5–7 min. As an added benefit, this arrangement also provides for suspension of the Zn flake in the reactor; in the event of an agitator failure, operation of the loop allows for safe, uninterrupted continuation of the batch. Adamantane bridgehead hydroxylations with nitric acid alone, even in its most concentrated form (100% HNO3, fuming) are not synthetically useful, requiring a large excess of reagent with long reaction times and are accompanied by virtually complete O-nitration: Vodička, V.; Isaev, S. D.; Burkhard, J.; Janků, J. Coll. Czech. Chem. Commun. 1984, 49, 1900–1906. Muspratt, J. S.; Hofmann, A. W. Justus Liebigs Ann. Chem. 1846, 57, 201–224. Ward, E. R. Industrial Mixed Acid Nitrations. Ambix 1976, 23, 199–200. Straessler, N. A. Synth. Commun. 2010, 40, 2513–2519. The heat generated through mixing HNO3 and concentrated H2SO4 in various proportions and with different amounts of water present has been extensively studied, e.g.: Urbanski, T. Chemistry and Technology of Explosives, Eng. Transl. by Jeczalikowa, I., Laverton, S.; Pergamon Press: London, 1964: Vol. I, pp 1−49. Lyubimova, V. A.; Kunin, T. I. Mechanism of thermal decomposition of sulfuric–nitric acid mixtures. Trudy Ivanovsk. Khim.-Tekhnol. Inst. 1958, 7, 5–11. Ross, D. S.; Gu, C.-L.; Hum, G. P.; Malhotra, R. Int. J. Chem. Kinetics 1986, 18, 1277–1288. Waterlot, C.; Haskiak, B.; Couturier, D. J. Chem. Res. (Synopses) 2000, 106–107. Hughes, E. D.; Ingold, C. K.; Reed, R. I. Nature 1946, 158, 448–449. Ingold, C. K.; Millen, D. J.; Poole, H. G. Nature 1946, 158, 480–481. Highly energetic nitrate esters: E.g., Wilt, P. E., III; Young, A. A. Process for the Manufacture of Explosive Nitric Esters. Atlas Powder Company, Wilmington, DE, U.S. Patent 2,883,414, 1959. Chavez, D. E.; Hiskey, M. A.; Naud, D. L.; Parrish, D. Angew. Chem., Int. Ed. 2008, 47, 8307–8309. Strojny, E. J.; Iwamasa, R. T.; Frevel, L. K. J. Am. Chem. Soc. 1971, 93, 1171–1178. 186 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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56. Kevill, D. N.; Hawkinson, D. C. J. Org. Chem. 1990, 55, 5394–5399. 57. Nitrous gases (NOx) of varying oxidation states (NO, NO2, N2O3, N2O4, N2O5) are strong oxidizers which can pose explosive hazards when in contact with organic substances or hydrocarbons in condensed phases (c.f.: Feb/1990 Shell Berre olefin steam cracker explosion: Grenoble, D. C. AIChE Spring National Meeting, Conference Proceedings, New Orleans, LA (U.S.A), 2004; pp 389–398). 58. NOx are highly toxic, regulated pollutants that require strict exposure controls (e.g., EPA 456/F-99-006R, 1999). Threshold Limit Value (TLV) for NO: 25 ppm; NO2: 3 ppm. 59. In oxidation reactions with HNO3, formation of nitrate esters from alcohols proceeds as a slower secondary process that requires excess reagent. C.f.: Hinkamp, J. B.; Sugimoto, R.; Dittmar, H. R. Manufacture of Amyl Nitrate. Ethyl Corporation, New York, NY, U.S. Patent 2,618,650, 1952. 60. HPLC analysis of the crude reaction mass post reaction completion against an authentic sample of nitrate ester derived from 12 (prepared using of a large excess of HNO3 and purified by flash chromatography) confirmed complete absence of the by-product. Differential Scanning Calorimetry (DSC) showed onset of a large decomposition exotherm at 150 °C. 61. Olah, G. A.; Lin, H. C. J. Am. Chem. Soc. 1971, 93, 1259–1261. 62. Olah, G. A.; Ramaiah, P.; Rao, C. B.; Sandford, G.; Golam, R.; Trivedi, N. J.; Olah, J. A. J. Am. Chem. Soc. 1993, 115, 7246–7249. 63. This reagent is also known as nitrosylsulfuric acid (CAS 7782-78-7). 64. Fitzpatrick, J.; Meyer, T. A.; O’Neill, M. E.; Williams, D. L. H. J. Chem Soc., Perkin Trans. 2 1984, 1984, 927–932. 65. Granger, J.; Sigman, D. M. Rapid Commun. Mass Spectrom. 2009, 23, 3753–3762. 66. Hughes, M. N.; Lusty, J. R.; Wallis, H. L. J. Chem. Soc., Dalton Trans. 1978, 530–534. 67. Dinitrogen monoxide (N2O) is an inert, non-flammable gas of very low reactivity under standard conditions. For regulatory purposes, it is not included in the definition of nitrous gases (NOx). N2O (known as E942) is used as an aerosol propellant for certain foods. 68. Due to its low reactivity towards nitrate/NO2+, urea is frequently used to remove trace nitrite/ NO+ from commercial nitric acid (c.f.: Ref. (62)).

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