Patent Review of Manufacturing Routes to Fifth ... - ACS Publications

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Patent Review of Manufacturing Routes to Fifth-Generation Cephalosporin Drugs. Part 1, Ceftolozane David L. Hughes* Cidara Therapeutics, Inc., 6310 Nancy Ridge Dr., Suite 101, San Diego, California 92121, United States ABSTRACT: Over 50 cephalosporin drugs have been approved over the past five decades, nearly half of all approved antibacterial drugs. Three new cephalosporins, classified as fifth generation for the treatment of serious Gram-negative bacterial infections including methicillin-resistant Staphylococcus aureus (MRSA), were recently approved. The current article summarizes the current status of antibacterial R&D and government actions to incentivize antibacterial research, provides a brief history of the development of cephalosporin antibacterials, and reviews the patent literature on synthetic routes and final forms of ceftolozane, a cephalosporin drug that was approved in the U.S. in Dec 2014.

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his article continues a series of reviews of the patent literature on synthetic routes to recently approved drugs, which have thus far covered oncology and HIV drugs.1 The subject of this and upcoming reviews is antibacterials. The current article is divided into three parts: (1) an introduction to this series on antibacterials with a synopsis of the current status of antibacterial R&D and government actions to incentivize antibacterial research, (2) a brief history of the development of cephalosporin antibacterials, and (3) a review of the patent literature on synthetic routes and final forms of ceftolozane, a cephalosporin drug that was approved in the U.S. in Dec 2014. This will be followed with part 2 covering two other recently approved cephalosporins, ceftaroline and ceftobiprole. These three cephalosporin drugs are classified as fifth-generation cephalosporins for the treatment of serious Gram-negative bacterial infections and are currently the only β-lactam antibacterials that are effective for treating MRSA infections.

Chart 1. Approval of Antibacterial Drugs by Decade

1. ANTIBACTERIAL R&DA PIPELINE THAT IS “FRAGILE AND WEAK” 1.1. The Problem: Declining R&D in Infectious Diseases. Antibacterial research was a major focus of R&D from the inception of the modern pharmaceutical industry in the 1930s through the 1980s, but as shown in Chart 1, approvals of new antibacterials began declining in the 1990s and have remained at a low level since the start of the 21st century.2 This decline is occurring at a time when increasing resistance to current drugs have raised fears that health authorities will soon be facing bacterial infections for which no drugs are effective. According to a 2013 report by the Centers for Disease Control and Prevention, more than 2 million people in the U.S. contract resistant infections each year, resulting in 23 000 deaths annually with costs to the healthcare system amounting to $20 billion.3 Worldwide deaths due to resistant infections are estimated to be 700 000 per year.4 The decrease in R&D and new drug approvals in infectious diseases might be attributed to several factors, but a major driver has been the much greater financial opportunities that have opened up in other therapeutic areas, primarily oncology. Historically, antibiotic drugs have been commercially successful. In year 2000, broad and enhanced antibacterials

were the third largest selling therapeutic category after antidepressants and antiulcer drugs. Five of the top 50 bestselling drugs in the U.S. in 2000 were antibacterials, including Augmentin (#12), Cipro (#19), Zithromax (#20), Levaquin (#30), and Biaxin (#46).5 Augmentin, with sales of $1.8 billion in 2001, was the second largest selling drug for GlaxoSmithKline that year.6 On the other hand, oncology drugs as a group were not even included in the list of top 25 therapeutic categories in year 2000.5 The approval of Gleevec in May 2001 for the treatment of chronic myelogenous leukemia (CML) began a major paradigm shift in the pharmaceutical industry. Gleevec was a revolutionary drug on many levels. First, it was the first truly effective oncology drug and had few serious side effects. A disease that nearly always resulted in quick death became one that could be controlled as a chronic condition.7 Second, Gleevec demonstrated that individual cancers were treatable with a drug that targeted a specific vulnerability of the cancer cell rather than the “carpet bombing” approach of earlier drugs that killed healthy cells as well as cancer cells. Third, Gleevec demonstrated the

© 2017 American Chemical Society

Received: January 27, 2017 Published: February 28, 2017 430

DOI: 10.1021/acs.oprd.7b00033 Org. Process Res. Dev. 2017, 21, 430−443

Organic Process Research & Development

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American healthcare system was willing to pay high prices for effective cancer drugs. Priced initially at $3346 per month, annual price increases averaging 7.5% per year brought the monthly price to $8479 in 2014.8 The industry took notice R&D shifted away from the therapeutic focus of the 1980s and 1990s (infectious disease, ulcers, and mental health) to oncology. As new cancer therapies were being developed during the 2000s, the regulatory environment was also quite different for cancer therapies compared to infectious disease. Since outcomes for cancer patients were so poor, incremental improvements in therapy could provide a basis for approval. In addition, cancer therapies traditionally had severe side effects, so drugs that were effective treatments could get approved even with debilitating side effects. On the other hand, the regulatory environment for antiinfectives was becoming increasingly challenging.9 Placebocontrolled clinical trials cannot be conducted in infectious diseases since all patients must receive active treatment. As such, clinical trials are designed to demonstrate noninferiority of the new drug to existing therapy. While it may seem easy to demonstrate a drug candidate is just as good as current therapy, cures can be close to 90% for existing antibiotics and clinical trials may require large numbers of patients to demonstrate noninferiority, depending on the statistical margin required.10 Two antibacterials failed to receive FDA approval, dalbavancin in 2007 and oritavancin in 2008. Pfizer abandoned dalbavancin, selling the rights to Durata Therapeutics. Likewise, Targanta Therapeutics sold the rights to oritavancin to The Medicines Company. To their credit, the FDA instituted more favorable guidelines for bacterial skin infections,11 and both of these drug candidates were shepherded through additional clinical trials by the new owners and gained U.S. approval in 2014. Nonetheless, by this time, the pharmaceutical industry had moved on to better opportunities. The favorable regulatory environment and opportunities for huge financial returns in oncology rapidly changed the focus of the pharmaceutical industry. By year 2015 not a single antibacterial was listed in the top 100 selling drugs worldwide compiled by First Word, compared to 19 oncology drugs.12 Cubicin (daptomycin), currently marketed by Merck, was the top selling antibacterial in 2015 with sales of $1.1 billion.13 The limited uptake of five antibacterials launched in the early 2000s, presented in Chart 2,14 is indicative of the weak launches and overall poor return on investment for new antibacterials as compared to Gleevec. One reason for the lack of significant revenue generated by antibacterials is the relatively low reimbursement. Current antibacterial treatments range from $2000 to $6000 per course of therapy.15 The older generic drugs are far cheaper and are effective in cases that do not involve a resistant infection, so these are used as first line treatment. Further, due to a concern with bacterial resistance, newly introduced antibacterials are used sparingly and generally only as a last resort when older treatments have failed. These drugs become more widely used only as resistance builds in older therapies. Thus, revenues may become significant only as patent expiration approaches, at which point generic competition will rapidly erode sales for the innovator company.15 By contrast, while new therapies in cancer may also be relegated to second or third line treatments at the time of approval, the much higher price8 and longer duration of therapy

Chart 2. Cumulative U.S. Revenues of Antibacterial Launches Compared to Gleevec14

generally lead to meaningful revenues and recoup of development costs for oncology drugs soon after approval. 1.2. Reinvigorating Antibacterial R&D. Given the significant medical threat posed by increasingly resistant bacteria, the U.S. government has incentivized antimicrobial R&D with a number of initiatives. 1. The Biomedical Advanced Research and Development Authority (BARDA) was established in 2010 with a mission to develop medical countermeasures against intentional or natural threats to public health, including emerging infectious disease. By Dec 2015, BARDA had awarded eight grants totaling $875 million to pharma companies to fund early and late stage clinical development of novel antibacterials and antivirals.15 2. The Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act was signed into law by President Obama on July 9, 2012. For drugs that are designated as qualified infectious disease products (QIDP) under this law, incentives include fast track status with increased access to the FDA during drug development, priority review of the NDA, and an additional five years of market exclusivity.16 On May 23, 2014, the FDA approved the first QIDP drug, Dalvance (dalbavancin), an antibacterial drug developed by Durata Therapeutics. Over a 10 month period from May 2014 to Feb 2015, six new antibacterials were approved, all under the GAIN program.17 As of June 2016, the FDA had granted 107 QIDPs to 63 different molecules.18 3. The 21st Century Cures Act, signed into law by President Obama on Dec 13, 2016, provides additional incentives for antimicrobial R&D. The law includes the Antibiotic Development to Advance Patient Treatment (ADAPT) Act that permits the FDA to approve antibacterial drugs to treat serious or life-threatening infections based on small clinical trials, combined with restricted product promotion.19 The Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms (DISARM) provision provides additional reimbursement for the use of approved DISARM products for serious infections.15 Even with the new incentives, Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at the 431



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Scheme 1. Lilly Process for the Conversion of Cephalosporin C to 7-ACA

intellectual property (IP) ownership would not be as important in driving revenues and profits.22 In summary, bacterial infections are becoming an increasing threat to human health as the advance of resistant organisms is outpacing the development of effective new antibacterials. Over the past two decades, pharmaceutical R&D in infectious disease has declined in favor of more lucrative targets, primarily oncology. A number of incentives for antibacterial research have been implemented by governments worldwide. Bolder initiatives have been proposed, but achieving these broader goals will require unprecedented cooperation and commitments among international governments, small and large pharma companies, and academia.

FDA, described the pipeline for new antibacterial drugs as “fragile and weak,” at a June 2016 Congressional hearing on antibacterial resistant “superbugs.”18,20 To put this into perspective, Joe Larson, deputy director of BARDA, noted that 37 antibacterial drug candidates are in Phase 2 and Phase 3 development in the U.S. compared with over 500 in oncology.20 This also indicates that nearly half of the 63 compounds that have been given QIDP status are in the earliest stages of development. Woodcock identified a number of initiatives to accelerate antibacterial development:18,20 1. Develop rapid diagnostics and identify new biomarkers to differentiate bacterial and virus infections to avoid prescribing antibacterials to patients who do not need them and to pinpoint the best treatment for the patients who do; 2. Form a clinical trial network with common protocols to quickly identify appropriate patient groups; 3. Launch a new program, Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), to provide funding for R&D at small pharmaceutical companies and academic centers to advance drug candidates from preclinical development through Phase 1. A report entitled “Securing New Drugs for Future Generations: The Pipeline of Antibiotics,” commissioned by the UK government and often referred to as the O’Neill Report, urges bolder actions:21 1. Provide significant financial incentives such as billion dollar prizes or guaranteed annual revenue for new antibacterials that meet prespecified unmet needs. Not only would this compensate for the low revenues generated during the early launch years, but it would also eliminate the aggressive marketing promotion that contributes to overuse and spread of resistance; 2. Launch a global innovation fund of $2 billion over 5 years to fund innovative research into drugs and diagnostics; 3. Drive more efficient drug development through common protocols for clinical trials and regulatory harmonization. Regarding financial incentives, to avoid a large one-time payment for a drug that may ultimately prove to be ineffective or unsafe, a staged approach has been proposed where the initial payment would cover development costs and subsequent pay outs would be based on clinical effectiveness, safety, and resistance profile.22,23 An additional benefit to these financial incentive models would be to foster data sharing since

2. DEVELOPMENT OF CEPHALOSPORIN DRUGS. A BRIEF HISTORY 2.1. Cephalosporin Discovery. The cephalosporin chronicle began some 70 years ago, when Italian scientist G. Brotzu discovered that the mold Cephalosporium acremonium, cultured from seawater near a raw sewage outlet, contained compounds that were active against Salmonella typhi, the bacterium that causes typhoid fever.24 During the 1950s, Abraham, Newton, and co-workers at Oxford isolated a number of compounds from the Cephalosporium broth, including a series of five closely related compounds they named cephalosporin P1−P5, as well as individual compounds cephalosporin C and cephalosporin N.25 This team definitively determined the structure of cephalosporin C in 1961 based on the IR spectrum, elemental analysis, and creative degradation studies.26 Cephalosporin C was not sufficiently active to be developed as an antibacterial drug, having only about 0.1% of the activity against Staphylococcus aureas as benzyl penicillin.25d,g However, cephalosporin C had improved stability in acidic solution relative to penicillin and was resistant to degradation by penicillinase, two key attributes that suggested analogs of cephalosporin C could have advantages relative to the penicillin drugs that had already gained wide use. As the first cephalosporin drugs became available, an important third property emerged, that far fewer patients experienced the serious allergic reactions common with penicillins. 2.2. Enabling the Synthesis of Cephalosporin Drugs: 7-ACA. By the time the structure of cephalosporin C was determined in 1961,26 it was already known that the amide hydrolysis product of penicillin, 6-aminopenicillanic acid (6APA), could be prepared by fermentation via the enzymatic hydrolysis of penicillin.27 This intermediate was proving valuable as a scaffold for making new penicillin analogues with improved properties. The corresponding amide hydrolysis 432



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Scheme 2. Biocatalytic Conversion of Cephalosporin C to 7-ACA

Scheme 3. Route to GCLE from Penicillin G

amine followed by insertion of the amide carbonyl to generate the intermediate imino ether 2. Initial attempts used aq. HNO2 for diazotization, but no 7-ACA could be isolated under these conditions. While it is not easy to troubleshoot a reaction that affords 0% yield, the group determined that 2 mol of nitrogen were being released in the reaction, suggesting that 7-ACA was likely being formed but the newly formed amine was decomposing by a reaction with HNO2 during the hydrolysis step. This ultimately led to experiments with volatile NOCl, an oxidant that could be readily removed by evaporation prior to aq. hydrolysis. The initial process, which was conducted in acetic acid as solvent, resulted in an isolated yield of 7-ACA of 7%. As often happens once the first breakthrough is realized, improvements quickly follow. When the solvent was changed to HCOOH, a solvent in which cephalosporin C had greater

product of cephalosporin C, 7-aminocephalosporanic acid (7ACA), however, could not be prepared by fermentation with the technology available at that time, so a chemical route was required. This proved quite challenging. In 1961 the Abraham and Newton team was able to secure a small amount of 7-ACA by acidic hydrolysis of 2 g of cephalosporin C with 1 N HCl followed by isolation via ion-exchange chromatography, affording 40 mg of crude 7-ACA.28 In parallel to this work, process chemists at Eli Lilly recognized that a scalable route involving direct amide hydrolysis was not going to be feasible given the lability of the beta-lactam ring. Their efforts focused on the activation of the amide to generate a structure that could be readily hydrolyzed under mild conditions.29 The innovative two-step process (Scheme 1) they published in 1962 involved treatment of cephalosporin C with NOCl, which diazotizes the 433



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Figure 1. Five generations of cephalosporin drugs, 1964−2015.

solubility, the yield improved to 40%.30 The use of CH3CN or nitroalkanes as solvent afforded 50% yield, and quenching residual NOCl with MeOH avoided the need to concentrate to dryness.31 With a process now available to produce 7-ACA, the medicinal chemists at Lilly were able to prepare and evaluate a variety of amide side chains, ultimately leading to the selection and clinical development of Keflin (cefalotin or cephalothin). In a remarkably short three years after the structure of cephalosporin C was published, Keflin was approved as the first cephalosporin drug in 1964. Process development for the conversion of cephalosporin C to 7-ACA continued, and by 1969, a route with an overall yield >90% was developed which involved silylation of the carboxylic acid and amine groups, conversion of the amide to an imino chloride using PCl5, followed by hydrolysis.30,32 In the 1980s a two-step enzymatic route was developed (Scheme 2), which allowed for the use of crude cephalosporin C, and today most of the 7-ACA is manufactured via the biocatalytic route.32−34 In the first step of the enzymatic process, CPC is oxidatively deaminated to keto-adipoyl-7-ACA using D-amino acid oxidase (DAAO). Peroxide is released in this reaction inducing a nonenzymatic oxidative decarboxylation to glutaryl-7-ACA. In the second enzymatic step, GL-7ACA acylase hydrolyzes glutaryl-7-ACA to produce 7-ACA and glutaric acid. Boehringer Mannheim developed a highly efficient

process using DAAO immobilized on an organic polymer and GA immobilized on an inorganic polymer, providing 94% conversion in step 1 and 96% conversion in step 2, each with just 30 min reaction time.35 2.3. Enabling Synthesis of Cephalosporin Drugs: GCLE. By year 2000 it was estimated that about 2 million kg of 7-ACA were produced worldwide.34 While 7-ACA was the starting material for many early cephalosporin drugs, the more complex drugs that were being synthesized starting in the 1980s required a more versatile starting material, 3-chloromethyl-7phenylacetylamino cephalosporanic acid p-methoxybenzyl ester (GCLE). The allylic chloride of GCLE allows for the ready modification of the 10-position, while the protected carboxyl group opens up a wider range of chemistries to build structural diversity at other positions of the molecule. GCLE is manufactured starting with penicillin G potassium salt. The chemistry to convert penicillin to the cephalosporin ring structure was established in the 1960s by Morin’s team at Eli Lilly.36 The route described in Scheme 3 builds from that early work and is indicative of the common sequence of transformations and reagents for this chemistry, although many variations exist.37 The route begins with the protection of the carboxylic acid of penicillin G as its PMB ester 3. The PMB protecting group is preferred since, once the cephalosporin of interest is synthesized, the PMB group can be cleaved as a final step 434



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Scheme 4. Medicinal Chemistry Route to Ceftolozane

had become widespread due to evolution of bacterial βlactamase enzymes, which hydrolyze the β-lactam ring to render the drugs ineffective. The cephalosporins that are grouped into second-generation drugs had several different modifications, but one significant motif was the introduction of an α-alkoxyimino group into the side chain, with cefuroxime as a representative of this generation. The methoxyimino group increases stability toward β-lactamase by 100-fold with the Zoxime nearly 20 000-fold more stable than the E-oxime.40 The third-generation drugs often incorporated even more bulky alkoxyimino side chains for greater stability against βlactamase and an aminothiazole side chain, as shown with cefotaxime, which provided improved activity against Gramnegative organisms. The third-generation cephalosporins also saw the introduction of zwitterions that increased activity against Gram-negative bacteria via drug penetration into the outer membrane of the bacteria. The zwitterionic motif is more common in the fourth- and fifth-generation cephalosporins (cefpirome and ceftolozane), which have improved efficacy against resistant organisms. The fifth-generation cephalosporins are broad spectrum drugs that are also active against methicillin-resistant Staphylococcus aureus (MRSA) infections.39 In addition to building stability to β-lactamase enzymes within the cephalosporin drug itself, an alternate strategy has been to combine an antibacterial drug with a separate drug that is designed to inhibit the bacterial β-lactamase enzyme. Two drug combinations have been recently approved: Zerbaxa, a combination of ceftolozane and tazobactam discussed below, and AVYCAZ, a combination of the third-generation cephalosporin ceftazidime and a new β-lactamase, avibactam.

under nonaqueous acidic conditions (TFA) that are compatible with the delicate cephem structure. In the next step, the sulfur is oxidized to the sulfoxide 4 with peracetic acid. The sulfoxide is in equilibrium with the ring-opened sulfenic acid 5, which is trapped with 2-mercaptobenzothiazole to form 6 and then converted to thiosulfonate 7 using benzenesulfinic acid. Chlorination affords the allylic chloride 8, which is ring-closed to the six-membered ring with ammonia in DMF, which is proposed to occur by deprotonation at the 4-position followed by SN2 displacement of the resulting carbanion at sulfur to release benzenesulfinate. Ammonia is a unique base for this transformation with a yield of 93%, much higher than the other bases screened, including NaOAc (29%), Et3N (18%), KOH (17%), and KI (14%).37a 2.4. Classification of Cephalosporin Drugs. Given the large number of cephalosporin drugs that were approved in the two decades after introduction of Keflin, in 1987 Williams introduced a classification system based on microbiologic profiles, with the intent to provide the prescribing physician a selection of appropriate drugs based on intended treatment.38 Cephalosporins are now classified according to “generations,” which have reached five, with some 50 cephalosporin drugs approved. In their incisive review of the “human chemical evolution” of antibacterials, Myers and co-workers describe the structural modifications that enabled the progression of cephalosporins through each generation.24 A modified version of the structural progression of cephalosporins is provided in Figure 1. The first-generation cephalosporin drugs were primarily active against Gram-positive bacteria such as Staphylococci.39 By the 1970s resistance to the first-generation cephalosporin drugs 435



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3. CEFTOLOZANE

Scheme 5. Medicinal Chemistry Route to Pyrazole Side Chain 2

Zerbaxa, a combination of ceftolozane and tazobactam, was approved in the U.S. in Dec 2014 and the EU in Sep 2015 for the treatment of complicated urinary tract infections and complicated intra-abdominal infections. Zerbaxa was the fourth new antibacterial drug approved by the FDA in 2014, which also included Dalvance (dalbavancin) in May, Sivextro (tedizolid) in June, and Orbactiv (oritavancin) in August.41 Ceftolozane is a fifth-generation cephalosporin antibacterial for the treatment of infections caused by Gram-negative bacteria that are resistant to conventional antibacterials, including multidrug resistant P. aeruginosa and β-lactamresistant Enterobacteriaceae. Tazobactam is an older βlactamase inhibitor that was first approved as a combination with piperacillin in 1994.41 Ceftolozane was discovered by Astellas Pharma and Wakunaga Pharmaceuticals. Calixa acquired the rights to ceftolozane (CXA-101) from Astellas and initiated development as a combination with tazobactam. Cubist acquired Calixa in 2009 and, in 2013, bought out the rights to ceftolozane from Astellas, giving Cubist global rights. In Jan 2015 Merck acquired Cubist. 3.1. Medicinal Chemistry Route to Ceftolozane. The composition of matter patents describe two routes for the synthesis of ceftolozane from commercially available ACLE, depending on the order of coupling of the two side chains to the β-lactam core. Only the sequence presented in Scheme 4 is exemplified in the patents42 and presented in the publication from the Astellas team.43 The synthesis began with the activation of the thiadiazolyl-oximinoacetic acid side chain 9 with MsCl and K2CO3 in DMA at 10 °C followed by coupling with the 7-amino group of ACLE with Et3N in EtOAc/water at pH 6 to afford 10 in >95% yield after crystallization from diisopropyl ether. The substitution of the allylic chloride with the bis-protected pyrazole 11 was accomplished using 1,3bis(trimethylsilyl)urea (BSU) and KI in DMF to furnish protected ceftolozane 12 in 78% yield. Global deprotection of the t-Bu ester, trityl, 4-methoxybenzyl, and Boc groups with TFA/anisole in dichloromethane afforded the TFA salt of ceftolozane. Purification and conversion to the sulfate salt were carried out by treatment with HP20 resin, concentration, and crystallization of the sulfate salt upon the addition of sulfuric acid in EtOH/water, with an overall yield of 58% from ACLE. The pyrazole side chain 11 was prepared as outlined in Scheme 5.42 5-Amino-1-methylpyrazole (13) was treated with NaNO2/HCl in water at 5 °C to provide the nitrosopyrazole 14, which was hydrogenated to the corresponding amine 15 in 73% yield for the two steps. The less hindered 4-amino group was selectively reacted with phenylchloroformate to furnish benzylcarbamate 16 in 78% yield. The 5-amino group was protected with a trityl group in 86% yield, followed by reaction with Boc-ethylenediamine to generate the side chain 11 in 95% yield.

3.2. Process Routes to Ceftolozane. Three process routes to ceftolozane are described in patent applications from Cubist and Merck. 3.2.1. Process Route One: From GCLE. The first route, described in four Cubist/Merck patent applications, follows the same steps as the Medicinal Chemistry route starting with GCLE. The experimental sections provide a level of detail uncommon in most patents, offering insights into the challenges of the chemistry and with workup/purifications. 3.2.1.1. Conversion of GCLE to ACLE. Although ACLE is a commercially available material, its preparation has not been well-documented in the literature. The hydrolysis of the side chain of GCLE is described in a granted patent44 and three patent applications from four separate companies.45−47 Each follows a process similar to that developed for the cleavage of the cephalosporin C side chain, namely, the formation of an imino-chloride followed by hydrolysis. The Merck U.S. Patent Application 2016/017689747 describes the process on a 270 kg scale (Scheme 6).47 Phosphorus pentachloride (2.0 equiv) was added to dichloromethane and cooled to −10 °C; then pyridine (2.0 equiv) was slowly added maintaining the temperature below 5 °C. GCLE (1.0 equiv) was added at a temperature of −10 to 0 °C; the cold temperature was important to minimize epimerization of the C7-amino center of the β-lactam. When this reaction was carried out as described, no epimer was detected in the resulting isolated ACLE-HCl. When this reaction was carried out at 35−40 °C, 2.8% of the epimer was formed.47 After cooling to −10 to −20 °C, i-BuOH (2 equiv) was added, presumably forming the imino-ether 19 (Scheme 6). The low temperature was required to minimize conversion back to GCLE. The reaction was quenched cold with EtOH/water to hydrolyze the imino-ether to the amine, ACLE. After the layers were separated, the organic layer was concentrated; then EtOAc was added to crystallize ACLE as its HCl salt in 87% yield and >97% purity. The major impurity in the crystallized product (0.8 to 1.0%) was the 2-Cl-PMB product in which electrophilic addition of chlorine has occurred in the position ortho to the methoxy 436



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Scheme 6. Manufacturing Process for the Conversion of GLCE to ACLE-HCl

group. Since this moiety is also cleaved during the TFA deprotection, it is not of consequence. The Merck patent includes three composition of matter claims: (1) ACLE with GCLE; (2) ACLE with GCLE and 2-ClPMB impurity, and (3) ACLE with the 2-Cl-PMB impurity.47 While ACLE is an older compound that could not be patented, the Merck strategy is to patent mixtures which have not been previously described. If these claims are granted, then many current manufacturers of ACLE may infringe this patent. The procedure for the preparation of ACLE was published in a 2005 Chinese patent application, but ACLE was not claimed.45 Since this procedure is quite similar to that provided in the Merck patent, the product likely also contains the compositions included in the Merck claims. This patent may be considered prior art if it can be shown that the procedure described generates the same profile as the Merck patent application. Therefore, it remains to be seen if the composition of matter claims will be granted in the Merck patent or challenged if the patent is granted. Although the major discovery of the Cubist/Merck group was minimizing epimer formation by maintaining a low temperature during iminochloride formation, no composition of matter claims were filed associated with this finding. 3.2.1.2. Conversion of ACLE to Intermediate 10 Toluene Solvate. The coupling of the thiadiazolyl-oximinoacetic acid side chain 9 to ACLE is described on a 99 kg scale in Merck PCT application WO 2016/025813 (Scheme 7).48 The side chain was activated as its mesylate in DMAc with K2CO3 at 3− 7 °C, a procedure which is also described in detail in a separate patent application.49 Work-up consisted of diluting with EtOAc and washing with 1.7% aq. HCl, followed by 10% aq. NaCl. The organic solution was then used for the coupling step, which was conducted as a two-phase system consisting of water/EtOAc at 0−5 °C, maintained at a pH of 3.2−3.8 with Et3N. Work-up consisted of the addition of solid NaCl and separation of the aqueous layer, followed by a NaCl wash. The organic layer was concentrated; then toluene was added, and

Scheme 7. Coupling of ACLE with Thiadiazolyloximinoacetic Acid Side Chain

the crystalline toluene solvate of 10 was isolated in overall 88− 92% yield with a wt % purity (solvent-free) of 99% (Scheme 7). The crystalline toluene solvate 10 is claimed.48 3.2.1.3. Conversion of Intermediate 10 to Ceftolozane Trifluoroacetate Salt. The reaction of 10 with the pyrazole side chain 11 (1.2 equiv) was carried out in NMP with BSU (3.6 equiv) and KI (1.8 equiv) at 27−30 °C (Scheme 8).50 The formation of the intermediate iodide was observed and monitored by an in-process assay. On a 150 kg scale, an improved yield (57% vs 48%) and purity (78% vs 75%) of 12 was obtained when the reaction was carried out with subsurface nitrogen purging vs just a nitrogen blanket. The authors attribute this to the removal of TMS-Cl or TMS-I byproducts, although no evidence was provided. Work-up consisted of the addition of CH2Cl2, then quenching with 4.4% aq. NaCl at 0−5 °C at pH 4−6, washing with sodium thiosulfate, then washing three times with 15% CF3CO2H, maintaining a temperature of 0−5 °C. The solution of the trifluoroacetate salt of 12 in CH2Cl2 was used for the next step. The assay yield of the solution at this stage was reported to be 65% on a 50 g run, which is higher than the 48− 57% yields reported at the 150 kg scale. The solution of the trifluoroacetate salt of 12 in CH2Cl2 was concentrated; then anisole (0.7 vol) and TFA (5 vol) were 437



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Scheme 8. Preparation of the Ceftolozane Trifluoroacetate Salt

Scheme 9. Conversion of ACLE-Imine to Ceftolozane Trifluoroacetate

added to effect deprotection of PMB, Boc, trityl, and t-Bu groups. Work-up consisted of charging the reaction mixture into CH2Cl2 at −35 °C and separating layers in what is described as a slow separation. The lower layer contained the product and TFA, while the upper layer consisted of CH2Cl2 and anisole. Acetonitrile was added to the product layer; then ceftolozane trifluoroacetate salt was crystallized by addition of MTBE to afford the product in 63% yield and 78% purity (HPLC area %) and 45% purity by weight. The authors provide normal operating ranges (NOR) and proven acceptable ranges (PAR) for the reaction and work-up.50 3.2.1.4. Conversion to Ceftolozane Sulfate Salt. The conversion of ceftolozane trifluoroacetate salt to the sulfalte salt is described on a 70 kg scale.50 To remove insoluble impurities, the trifluoroacetate salt was dissolved in water and pH adjusted to 6−7 with NH4OH. After stirring for 20 min, the

batch was adjusted to pH 1.5 with HCl and stirred for an additional 20 min. Perlite was added; then the batch was filtered. To remove nonpolar impurities, the filtered solution was passed through a column of HP20 resin at 24−26 °C and eluted with acidic water (pH 1.5). The rich cuts were adjusted to pH 6.4−7.0 with NH4OH at a temperature of 0−8 °C. The resin treatment upgraded the purity from 75−80% to 92−95 area %. The combined rich cuts were concentrated by membrane technology (nano- and dia-filtration) to about 80 g/L. The crystallization of the sulfate salt was accomplished by the addition of sulfuric acid (2.5 equiv) at 8−12 °C followed by 2-PrOH. The yield was not provided. The patent application lists 19 identified impurities and purging factors for the process.50 3.2.2. Process Route Two: Reversed Order. An alternate route (Scheme 9) described in U.S. Patent Application 2015/ 438



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Scheme 10. C−N Cross Coupling Approach to Ceftolozane

Work-up consisted of dilution with EtOAc, washing with cold NaHSO4, and filtering through Harborlite to remove Pd. The mixture was concentrated, then deprotected using anisole/ TFA. The isolation was altered relative to that described from the SN2 displacement (Scheme 8) since solids could not be isolated via that work-up. Instead, the isolation of the TFA salt of ceftolozane was accomplished by addition of toluene, cooling to −25 to −5 °C to produce a phase separation, then separation of the lower product-rich phase. Ceftolozane TFA salt was then precipitated by addition of either acetonitrile or MTBE. The overall yield was 78% with 90% purity. 3.3. Preparation of the Side Chains. Merck/Cubist patents provide improved processes for the preparation on the thiadiazolyl-oximinoacetic acid 9 and pyrazole 11 side chains. 3.3.1. Thiadiazolyl-oximinoacetic Acid Side Chain. The synthesis of the thiadiazolyl-oximinoacetic acid side chain is not described in the Medicinal Chemistry patents nor publication, but similar type compounds were published in a 1993 European patent application (Scheme 11).54 The disadvantages of this route include the length (eight linear steps), relatively low overall yield of 12%, and the high temperature (>200 °C) required to convert the trimethoxy nitrile 25 to the vinyl nitrile 26. An alternate route is described in a PCT Int. Patent Application WO 2016/100897 by Merck.55 This route starts with dimethyl malonate and requires eight linear steps and four isolations with an overall yield of 16−20% (Scheme 12). The first two steps, formation of oxime 32 and alkylation, were carried out without isolation. In step 3, the amidation of the diester with 25% aq. ammonia was selective when carried out at −5 to +5 °C. At the end of reaction aq. HCl was added to pH 5, resulting in the crystallization of amide ester 34 in 63−69% yield for the three steps and 94% purity. The dehydration of the amide to nitrile 35 was carried out in MTBE and concentrated to an oil after aq. workup. The conversion of nitrile 35 to amidine 38 was conducted in three steps carried out in a single pot in MeOH/water. Amidine 38 was crystallized from the reaction mixture after concentration and pH adjustment to 7, then recrystallized from MTBE in 45−60% yield. The amidine is very unstable so improved yields were obtained when the hydrolysis of methyl ester 37 was carried out at or below 0 °C.

0111853 from Merck starts with 20, the salicylaldehyde imine of ACLE,51 a commercially available material that is prepared from ACLE and salicylaldehyde.52 In this process, the two side chains are appended in the opposite order. The pyrazole side chain 11 was coupled first using KI and bis(trifluoromethyl)acetamide (BSA) in NMP to furnish trifluoroacetate salt 21 in 86% yield. This is a much improved yield relative to the 47− 65% yield for this step using 10 (Schemes 1 and 5). The thiadiazolyl-oximinoacetic acid side chain 9 was coupled by the reaction of the imine 21 with mesylate 22 at room temperature under highly concentrated conditions (1.75 vol solvent vs imine 21) in 24:1 (v/v) CH2Cl2−water. After complete reaction, the mixture was added to MTBE, resulting in the crystallization of 12 in 81% yield as its TFA salt. The conversion to ceftolozane followed the procedure described above, namely, global deprotection to the TFA salt followed by salt exchange and crystallization of the sulfate salt. Mesylate 22 and both isolated intermediates 12 and 21 are claimed.51 3.2.3. Process Route Three: C−N Cross Coupling of Pyrazole Side Chain. In the routes discussed thus far, the pyrazole side chain is appended via an SN2 displacement of an allylic chloride (using KI to convert to the iodide). The reported yield for this step in the Merck patents ranges from 47 to 86%, depending on scale and conditions. In the Medicinal Chemistry route, the yield ranges from 75 to 78%. As an alternate approach, PCT Int. Patent Appl. WO 2016/025839 from Merck describes improved yields of 92−96% for this bond formation via Pd-catalyzed cross coupling (Scheme 10).53 With the salicylaldehyde substrate 20, a cross-coupling yield of 95% was obtained (not shown). Optimized conditions for the cross-coupling were use of 1.1 equiv of the pyrazole 11, 1.5 equiv of CF3CO2K, THF as solvent (7 vol), tris(4-dimethylaminophenyl)phosphite (7%), and Pd2(dba)3 (1%) at room temperature. A transient intermediate was identified as the trifluoroacetate 23, which also converts to the coupled product. It was not clear if the reaction proceeds entirely via the trifluoroacetate or whether cross coupling occurs with both the trifluoroacetate and the chloride. 439



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step (Scheme 13).56 Starting with commercially available pyrazole 39, the amine was protected with a trityl group then

Scheme 11. Medicinal Chemistry Route to Imino-Ether Acid Side Chain

Scheme 13. Manufacturing Route to Pyrazole 11

the ester hydrolyzed. Crystallization from i-PrOAc afforded acid 40 in 80% yield. The acid was treated with diphenylphosphoryl azide (DPPA) and Et3N in toluene at 45 °C to generate the acyl azide 41. Work-up consisted of the addition of water, separation of layers, and drying the toluene layer by azeotropic distillation, keeping the temperature below 40 °C to avoid decomposition. Boc-ethylenediamine was added and the mixture heated to 90 °C for 4−5 h. Crystallization from ethanol afforded pyrazole 11 in 77% yield and 99.8% purity. As with other patents and patent applications regarding ceftolozane from Cubist/Merck, this application provides considerable experimental details including HPLC parameters and NOR/PARs for the chemical steps and isolations. 3.4. Regulatory Starting Materials (RSM) and Manufacturing Route. According to the European Public Assessment Report (EPAR), ceftolozane sulfate is manufactured from three starting materials in four stages, which are comprised of a number of substages.57 The same synthetic route was used for

The methyl ester must be hydrolyzed at this stage since the thiadiazole is not stable to hydrolysis conditions. Amidine 38 was converted to thiadiazole using NH4SCN and bromine in MeOH. The product was isolated by the crystallization after the addition of aq. HCl to pH 2.5. This was followed by recrystallization from THF/water/MTBE then recrystallization again from MeOH/water. The yield is reported from 50% to 80%. Overall, 106 kg of 9 was prepared from 200 kg of methyl malonate. A compound claim is made for amide ester 34. 3.3.2. Pyrazole Side Chain 11. A short synthesis of the pyrazole side chain is described in Merck patent application WO 2016/095860, employing a Curtius rearrangement as a key

Scheme 12. Manufacturing Route to Thiadiazolyl-oximinoacetic Acid Side Chain 8

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the manufacture of active substance for all clinical trials, registration stability studies, and nonclinical studies. Since no further information is provided, any of the three process routes could be the manufacturing routes with the RSMs as the βlactam ACLE or imine 20 and the side chains 9 and 11. 3.5. Final Form of Ceftolozane. According to the EPAR, ceftolozane sulfate “is mostly amorphous, containing some degree of crystallinity.”57 Since the API is dissolved during the manufacture of drug product, the polymorphic form was not considered a critical attribute. The proposed storage condition of the API is −20 °C.57 Two polymorphs of ceftolozane sulfate are reported by Calixa in U.S. Patent 8,906,898.58b Form 1 was formed upon crystallization of the sulfate salt from 2-PrOH/water and contained 18−20 wt % water. Drying under vacuum with a nitrogen bleed at 20−25 °C for 24−48 h afforded crystalline form 2, which contained 7−8% water. Dynamic vapor sorption experiments demonstrated that Form 1 transitioned to Form 2 as the relative humidity decreased from 40% to 20% at 25 °C, and some amorphous material was generated when the relative humidity dropped below 20%. Form 2 is claimed in the granted patent.58b The crystallization process is described on a 55 kg scale.58b The zwitterion was dissolved at 10 °C in water at 80 g/L followed by addition of 2.5 equiv of sulfuric acid. The solution was seeded to induce nucleation; then the mixture was stirred for 3 h. 2-Propanol (30 vol vs ceftolozane) was added to complete the crystallization. In the Medicinal Chemistry process, ceftolozane sulfate was crystallized from EtOH/water.42 Calixa found improved solution stability using the 2-PrOH/water system with 15% degradation vs 29% degradation with EtOH/water over 6 days (temperature and concentration not reported).58 Merck patent application WO 2016028670 describes and claims bromide, edisylate, mesylate, chloride, maleate, phosphate, and ketoglutarate salts of ceftolozane.59 After 4 weeks at 25 °C and 60% relative humidity the loss of purity was highest for the phosphate salt of ceftolozane at 13.7% and the lowest for the edisylate salt of ceftolozane at 1.7%. The edisylate, mesylate, chloride, and bromide salts had better solid state stability than the sulfate salt.59 3.6. Ceftolozane Summary. Three potential manufacturing routes to ceftolozane sulfate are described in patents granted to Merck starting from the β-lactam GCLE. The first process follows the same route as that described by the Medicinal Chemistry team with the additional development to improve scalability. The second route starts with the salicylaldehyde imine of GCLE and appends the side chains in the opposite order. The third route is a close variation of the first two, with implementation of a Pd-catalyzed C−N cross coupling as replacement for the SN2 replacement, resulting in higher yields for this step. Considerable experimental details are provided in the patents, providing unique insights of the challenges involved in purification and isolation of the sensitive β-lactam structures. Improved routes to the two side chains have also been described in patents assigned to Merck. The final form of the API is crystalline form 2 of the sulfate salt, which is rendered partially amorphous during drying. The API storage temperature is −20 °C. Salts with improved stability have been identified but have not replaced the sulfate salt as the approved form, which was used throughout clinical development and launch.

Review

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

David L. Hughes: 0000-0001-5880-8529 Notes

The author declares no competing financial interest.

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ABBREVIATIONS 7-ACA, 7-aminocephalosporanic acid; ACLE, (6R,7R)-4methoxybenzyl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylate; API, active pharmaceutical ingredient; BSA, bis(trimethylsilyl)acetamide; BSU, N,N′-bis(trimethylsilyl)urea; DMAC, N,N′-dimethylacetamide; EPAR, European Public Assessment Report; GCLE, 3chloromethyl-7-phenylacetylamino cephalosporanic acid pmethoxybenzyl ester; MTBE, methyl t-butyl ether; NMP, Nmethylpyrrolidinone; NOR, normal operating ranges; PAR, proven acceptable ranges; PMB, p-methoxylbenzyl; RSM, regulatory starting material

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REFERENCES

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