Article pubs.acs.org/OPRD
Development of a Manufacturing Route to Avibactam, a β‑Lactamase Inhibitor Matthew Ball,† Alistair Boyd,† Gareth J. Ensor,† Matthew Evans,† Michael Golden,*,† Simon R. Linke,† David Milne,† Rebecca Murphy,† Alex Telford,† Yuriy Kalyan,‡ Graham R. Lawton,‡ Saibaba Racha,‡ Melanie Ronsheim,‡ and Shao Hong Zhou‡ †
Pharmaceutical Technology and Development, AstraZeneca, Silk Road Business Park, Macclesfield SK10 2NA, United Kingdom Chemical Development, Forest Laboratories Inc., 45 Adams Avenue, Hauppauge, New York 1178, United States
‡
ABSTRACT: Process development work to provide an efficient, robust, and cost-effective manufacturing route to avibactam, a β-lactamase inhibitor is presented herewith. Aspects of this optimization work include the counterintuitive introduction of a protecting group to effect a difficult urea formation and the use of controlled feed hydrogenation conditions to facilitate an elegant one pot debenzylation and sulfation reaction. Overall, the commercial process delivers avibactam in much improved yield with significant reduction in the environmental footprint.
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Phase II Chemistry. The Novexel route that was used to supply Phase II clinical material is shown in Scheme 2. Key problems within the route were the potentially hazardous combination of sodium hydride and DMSO in the transformation of 2 to 6 and the wasteful onward processing of the undesired cis-isomer of 3 in the subsequent stage. The conversion of 3 to 4 proved difficult to scale; the introduction of the fragile electrophilic strained urea prior to treatment with nucleophilic reagents required to convert the ester moiety to the primary amide meant that yields were seen to fall as the process was scaled. Specifically, selective hydrolysis of the trans isomer of 9 required very careful control of temperature, pH, and time, which was difficult to achieve on scale. Consequently, manufacturing yields for the telescope procedure from 3 to 4 were less than 30%. Conversion of 4 to 5 was also far from ideal. The nonisolated debenzylated intermediate 10 is unstable, and the resulting degradation products appeared to poison the palladium catalyst, such that a very high catalyst loading (20% rel wt, of 10% w/w Pd/C) was required. The necessity of excluding water from the system also required that dry catalyst was used, which presented safety concerns and was expensive. Additionally, the environmentally unfriendly solvent system (DCM/DMF) was required to ensure solubility of 10 (to allow removal of the catalyst by filtration). This also introduced complications downstream, where a time-consuming and highly wasteful solvent swap from DMF to xylene was necessary to facilitate workup of the product 5. Handling of the highly moisture sensitive and noncommercial sulfating agent, sulfur trioxide N,N-dimethylformamide complex (SO3·DMF) was also problematic, but made necessary, since the reactivity of alternative (more stable) sulfur trioxide complexes were not sufficient to react with the weakly nucleophilic hydroxylamine 10. The procedure was however scaled to produce approximately 250 kg of 5 at 20 kg batch size with yields of approximately 55%.
INTRODUCTION Avibactam (1), a β-lactamase inhibitor,1,2 in combination with Ceftazidime (Zavicefta) has recently been approved by EMA for treatment of complicated intra-abdominal infections (cIAI), complicated urinary tract infections (cUTI), and hospitalacquired pneumonia (HAP), including ventilator-associated pneumonia (VAP). The EMA also approved Zavicefta for the treatment of infections caused by aerobic Gram-negative organisms in adult patients who have limited treatment options. Avibactam was originally developed by the Aventis infection division in Romainville (France), which later became Novexel. During the Phase II studies, however, commercial developments led to the project becoming a co-development between AstraZeneca and Forest Laboratories. At this stage in development, the cost of goods were significantly above the desired commercial targets and, similarly, the environmental sustainability of the chemistry required improvement; the process mass intensity (PMI)3 for the conversion of 2 to 1 (Scheme 1) was calculated at 6480 (meaning that 6480 kg of raw materials were required for each kg of avibactam produced), and a number of environmentally undesirable reagents and solvents were required. Key intermediates in the avibactam 1 synthesis are essentially unchanged throughout the development history and are shown in Scheme 1. The optimized synthesis currently in use is obtained through a linear sequence from the key intermediate 3, which is derived from a glutamic acid derivative 2. 3 is converted to the final intermediate 4, which is subsequently converted to the tetrabutylammonium salt 5 of avibactam. Isolation of the stable, crystalline tetrabutylammonium salt allows convenient processing and also provides input for a sterile salt exchange crystallization to give avibactam 1. Development of intermediate 3 has been crucial to the viability of the project and a more detailed discussion of the development of this chemistry from the commercially undesirable Medicinal Chemistry route4,5 to a route that produced multitonne quantities is described separately.6,7 © 2016 American Chemical Society
Received: August 10, 2016 Published: September 14, 2016 1799
DOI: 10.1021/acs.oprd.6b00268 Org. Process Res. Dev. 2016, 20, 1799−1805
Organic Process Research & Development
Article
Scheme 1. Key Intermediates in the Avibactam (1) Synthesis
Scheme 2. Synthesis Used to Supply Phase II Clinical Material
optimization of the process for making 3 was carried out. After much development, the key changes involved substituting the base (for potassium tert-butoxide) and optimization of the first step, improvement of the one-pot chloride displacement and oxime formation and overall increase in process efficiency by reducing volumes, extractions, and distillations. It was also found that isolation of the first intermediate 6 could be eliminated and that, surprisingly, the pure trans isomer of 3 could be isolated very cleanly by directly crystallizing the oxalate salt from a methanol/ IPA/ethyl acetate mixture.
Overall the process for manufacturing 5 (Scheme 2) was used to produce the (low) hundreds of kilograms necessary to support Phase II trials. However, due to the very low yields (overall yield of 1 was approximately 9% from 2), environmental concerns, and difficult (and lengthy) operability, the process was unsuitable for long-term commercial manufacture and needed to be redesigned.
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RESULTS AND DISCUSSION Fully Telescoped Route to 3. Building on earlier improvements (made by the Novexel team),4−6 further 1800
DOI: 10.1021/acs.oprd.6b00268 Org. Process Res. Dev. 2016, 20, 1799−1805
Organic Process Research & Development
Article
Scheme 3. Manufacturing Route to the Key Intermediate (3)
Ultimately, a fully telescoped procedure to a single isomer of 3 from 2 was realized7 (Scheme 3). This route was successfully scaled to 340 kg (input) scale to produce a total of 1080 kg of 3 in five batches with an overall yield of 56%. New Approach to Obtain 4 from 3. Having an efficient process for making pure trans 3 opened the door to new approaches to the synthesis of 4 that did not require the selective hydrolysis of the trans benzyl ester of 9. Attempts were made to optimize both the urea formation (3 to 9) and the ester to amide conversion (9 to 4), with little gain in yield or robustness. Pursuing an alternative strategy of reversing the steps of the reaction, formation of the amide 11 from 3 was achieved such that it was then possible to attempt to introduce the fragile urea bond after amide formation (Scheme 4). Fortuitously, the ammonium oxalate byproduct formed on mixing 3 with methanolic ammonia is highly insoluble in this reaction medium and can be removed by filtration. A solvent swap to toluene crystallizes the product 11, while solubilizing the benzyl alcohol byproduct. Yields of 92% were achieved, of very high quality material, on 170 kg (input) scale. Initially, attempts to form the urea 4 directly from 11 were unsuccessful. Triphosgene acted to dehydrate the primary amide to form the corresponding nitrile. Use of alternative phosgenating agents (such as CDI and various chloroformates) were unsuccessful but did reveal interesting selectivity between the two nucleophilic nitrogens in the molecule. Reaction of 11 with CDI gave a mixture of acylated products (roughly equal amounts in most solvents), but only reaction onto the hydroxylamine nitrogen would cyclize to form the desired product 4. Acylation of the piperidine nitrogen would only produce the hydantoin 12. A computational study of the reaction intermediates and their configurations has validated the practical work−the pathway to hydantoin is favored over urea formation. While CDI is seen to react (approximately) equally on both nitrogens, chloroformates are highly selective for reaction on the piperidine (>99:1 selectivity). Attempts to cyclize the resultant carbamate to form the urea were not successful, but it was realized that this selectivity could be effectively utilized as a protecting group strategy. Both BOC and FMOC protection can be readily achieved on the piperidine nitrogen, with subsequent
quantitative acylation of the hydroxylamine nitrogen with CDI. The much milder deprotection conditions required to remove the FMOC group meant that this group was likely to offer better operability than the BOC group, and thus, the FMOC approach was selected for further development. Deprotection of FMOC using diethylamine allows spontaneous cyclization to form the urea, and the addition of aqueous acid facilitates removal of the basic species and promotes crystallization. Introduction of protection and deprotection steps may seem an unusual strategy to pursue since it both lengthens the sequence and is atom inefficient; however, the telescope is operationally very simple (Scheme 5) and the individual steps are essentially quantitative. 3 is mixed with chlorobenzene and N,Ndiisopropylethylamine, and FMOC-Cl is added. The resulting FMOC protected species 13 is transferred to a vessel containing solid CDI. Diethylamine is added, followed by aqueous HCl, and the product 4 is filtered. The yield, robustness and operational advantages outweigh the aforementioned disadvantages, and yields of over 90% are achieved on commercial manufacturing scale, with a cycle time of
