Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

Materials science, while often associated with industries other than bio/pharmaceuticals, also plays a significant role in the production of drug substances and formulated products, from reactor and purification equipment design to catalyst technology, the selection of polymorphs, the development of new drug-delivery technologies, and the choice of materials for medical devices. A selection of developments in nanocatalysis for API synthesis and nanoparticle technologies for more effective API delivery is discussed here.


	Many types of nanocatalysts have been developed and investigated as mediators of complex synthetic organic transformations. They are attractive because nanoparticles have different properties from their bulk counterparts, including high surface areas. Their electronic, optical, and magnetic properties are often vastly different from bulk materials, and consequently their reactivities are different on many levels. Synthetic chemists have sought to use these different behaviors to prepare highly stable nanocatalysts with high activities and selectivities. Magnetic nanocatalysts are of particular interest in organic synthesis because they can often be readily recovered and reused, while the separation of non-magnetic nanocatalysts that are also non-supported can be problematic.

	Audrey H. Moores at McGill University in Canada focuses on the synthesis of novel magnetic, reusable metal nanocatalysts for coupling, hydrogenation, C-H activation, and oxidation. Robust, inexpensive, amphiphilic polymer-stabilized Fe(0) nanoparticle (Fe NP) catalysts developed by Moores are highly efficient for the hydrogenation of alkenes, alkynes, aromatic imines, and in ethanol or water in a flow reactor. Aliphatic amines and aldehydes, ketones, esters, arenes, and nitro and aryl halide groups are not affected (1). Nanocatalysts comprising Fe

 particles surrounded by nitrogen-doped graphene layers have also been shown by Matthias Beller of the Liebniz Institute for Catalysis and the University of Rostock in Germany to mediate the hydrogenation of structurally diverse and functionalized nitroarenes to anilines and the one-pot reductive amination of carbonyl compounds with nitroarenes (2). His group prepared more than 40 amines useful as building blocks for pharmaceuticals and other fine/specialty chemicals.

	Moores has also shown that patches of palladium nanoparticles deposited on colloidal cellulose nanocrystallite (CNC) nanowhiskers catalyze the enantioselective hydrogenation of prochiral ketones in water at room temperature and 4 bar H

, achieving an enantiomeric excess of 65% with 100% conversion (3). Meanwhile, researchers at Birjand University and Payame Noor University in Iran deposited ionic liquids (ILs) on magnetic nanoparticles to overcome their limited recyclability (4). This approach led to increased activity of the ILs and their reduced consumption, and the heterogeneous nanoparticles were recoverable. The researchers suggest that the nanoparticle-stabilized ILs can be used as solvents, catalysts, or for the extraction of specific compounds that form bonds with the ILs. 


	A large number of small-molecule drug candidates under development today have poor solubility, and thus reduced bioavailability. In many cases, formulation strategies and drug delivery technologies can overcome this issue. Nanoparticles in particular can increase the stability of APIs, protect them against degradation, and enhance their bioavailability by increasing their solubilization, enhancing their permeability, reducing their rate of metabolism, and/or improving their transport. 

	While biodegradable polymers are often selected for the formation of nanoparticles, some researchers have focused on the use of lipids due to their greater physiologic similarity. Solid lipid nanoparticles (SLNs) also offer site-specific targeting, with high adhesion to the gut wall, which is an ideal location for the absorption of release APIs (5). In addition, both lipophilic and hydrophilic drugs can be incorporated into SLNs without the need to use organic solvents. It is important, however, to select an appropriate lipid for a given API to obtain crystalline SLNs with uniformly dispersed API and suitable lipophilicity for improved drug solubility. In some cases, biodegradable polymers may be used as surfactants to stabilize SLNs or as a surface coating to increase the biodistribution of APIs. Other excipients may also be used in SLN formulations, including non-polymeric nonioninc surfactants, cosolvents, and antioxidants.


	As the potency of many drugs-particularly oncology APIs-increases, there is significant need for technologies that enable their targeted delivery to the site of action to minimize the unwanted side effects common with systemic delivery. Many researchers are turning to nanotechnology to achieve that goal. Careful design of nanoparticle properties, typically through modification of their surface properties, can enable their binding to specific components within the body and influence their API release behaviors.

	Two examples of the use of nanotechnology for targeted drug delivery come from Southern California-based universities. In the first example, scientists from the California NanoSystems Institute at UCLA developed a nanoparticle delivery system for the antibiotic moxifloxacin that vastly improves the drug’s effectiveness against pneumonic tularemia, a type of pneumonia caused by inhalation of the bacterium 

, which is highly infectious and designated as a top-tier bioterrorism agent (6), survives and multiplies within macrophages, particularly those in the liver, spleen, and lung. Jeffrey Zink and colleagues designed mesoporous silica nanoparticles that are readily taken up by macrophages. The nanoparticles are soaked overnight in a solution of the API, which is adsorbed in the pores. The pores are then blocked with nanovalves that are designed to degrade in the acidic environment of the macrophages. As a result, the drug is not distributed systemically, but only once it enters the macrophages. The approach allows for significantly more API to reach the site of infection without the side effects typically observed when moxifloxacin is administered freely into the blood stream (6). The researchers found that in mice given a lethal dose of 

, the nanoparticle-delivered moxifloxacin caused few side effects and was more effective at reducing the number of bacteria in the lungs than a dose of freely injected moxifloxacin two to four times greater.

	Researchers at the University of California, San Diego Jacobs School of Engineering, led by Liangfang Zhang, have taken a different approach to targeted delivery using nanotechnology. In their case, nanoparticles formed of a biodegradable polymer were coated with fragments of human platelet membranes, which preferentially bind to damaged blood vessels and certain pathogens, such as Methicillin-resistant 

 (MRSA) bacteria, and protect the nanoparticles from attack by the immune system (7). Unlike synthetic platelet mimics, the platelet membrane fragments possess the complete set of surface receptors, antigens, and proteins naturally present on platelet membranes. Once the platelet fragments bind to the desired site, the polymeric core degrades and is safely metabolized by the body, releasing the drug at the site of action. When nanoparticles loaded with docetaxel, a drug used to prevent scar tissue formation in the lining of damaged blood vessels, were administered to rats afflicted with injured arteries, the loaded nanoparticles were observed to selectively bind to the damaged sites of arteries and heal them (7). 

	Nanoparticles loaded with vancomycin at one-sixth the clinical dose and injected into mice systemically infected with MRSA bacteria resulted in up to a one-thousand-fold reduction of the bacterial counts than those in mice treated with the clinical dose of vancomycin alone (7).


	A third approach to nanoparticle-based delivery of APIs relies on the use of nanoparticles formed from natural biomolecules. Silk fibroin (SF) has attracted particular attention due to its excellent biocompatibility, biodegradability, and low immunogenicity combined with a high binding capacity for many types of drugs, good controlled release properties, and ease of preparation (8). SF is an alternative to biodegradable polymers, such as poly (lactic acid) (PLA), poly (ε-caprolactone) (PCL), and poly (glycolic acid) (PGA) because protein-based nanoparticles bear functional groups that are naturally designed to interact with cells and cause biological responses. SF in particular is widely used as a biomaterial and is well characterized and understood. Studies of SF nanoparticle systems have shown that its biodegradation rate is influenced by its crystallinity, molecular weight, and degree of crosslinking. However, while numerous methods for the fabrication of nanoparticles have been developed, there is significant variation in the structure of SF obtained from different species and even individuals, and thus interest in genetically recombinant SF-based nanoparticles is increasing. Surface modifications are also required to improve the delivery specificity (8).

	A nanoparticle-based formulation of the drug ormeloxifene (ORM) for the treatment of pancreatic cancer is under development by researchers at the Department of Pharmaceutical Sciences and the Center for Cancer Research at the University of Tennessee Health Science Center in order to enable tumor-specific targeted delivery (9). The ORM was readily encapsulated in poly(lactic-co-glycolic acid) nanoparticles that were then subjected to antibody/aptamer conjugation to achieve tumor-specific targeting. Cellular uptake and internalization studies with the 100-nm-diameter particles confirmed that they did not undergo lysosomal degradation and survived to allow efficient endosomal release. Treatment of a xenograft mice model resulted in increased animal survival and suppressed pancreatic tumor growth (9).

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	2. M. Beller et al., 

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:
	When referring to this article, please cite it as C. Challener," Nanotechnology Shows Promise for API Synthesis and Delivery," 

Articles

Nanoscale catalysts and engineered nanoparticles may have a big impact on small-molecule pharmaceuticals.

Nanotechnology  Shows Promise for API Synthesis and Delivery

Global demand for APIs is expected to increase at a compound annual growth rate (CAGR) of 6.5% from nearly $120 billion in 2013 to just under $186 billion in 2020, according to Transparency Market Research (1). APIs for drugs that treat cancer and central nervous system diseases will grow at the fastest rate, while those intended for the formulation of therapeutics for cardiovascular disease will account for the largest percentage of revenues. The growth of the oncology segment is driving demand for highly potent APIs (HPAPIs), which is predicted by Grand View Research to increase significantly from $12 billion in 2014 to $25.86 billion in 2022, which corresponds to an average annual growth rate of 14.4% (2).

	Despite these positive predictions, it appears that the number of approvals of new molecular entity (NME) and biologic license application (BLE) approvals by FDA may be down in 2015. A total of 30 NME and BLA approvals were granted through Oct. 27, 2015 (3,4), while 41 new drugs were approved in 2014 (5). In 2013, 29 NMEs alone were approved (6). On the other hand, as established blockbusters-both small- and large-molecule-continue to lose patent protection, opportunities for generics and biosimilars, respectively, have increased. In particular, with an approval pathway for biosimilars now established in the United States, this segment of the API market is expected to experience dramatic growth. Market research firm RNCOS predicts that the formulated biosimilar market, which it estimates was worth $1.89 billion in 2014, will grow at a CAGR of 54.4% to reach $25.53 billion in 2020 (7).


	The approval of the first biosimilar in the US in 2015 is a key event for the pharmaceutical industry. Zarxio, a biosimilar of Amgen’s Neupogen (filgrastim) received approval in March 2015 (8), but its launch was delayed until September 2015 due to a lawsuit filed by Amgen claiming lack of appropriate disclosure and patent negotiation on the part of developer Sandoz (the generic business of Novartis). Korea-based Celltrion is waiting on FDA’s decision regarding its biosimilar Remsima, which is a form of the rheumatoid arthritis drug Remicade (infliximab) marketed by Johnson & Johnson and Merck & Co. and is already approved in Europe.

	FDA also made an approval decision with the potential to have significant impact on drug development and manufacturing when it approved the first 3D-printed drug in 2015 (9). Spritam (levetiracetam) is a rapid-dissolving tablet for the treatment of epileptic seizures based on a highly prescribed medicine. The product is manufactured by Aprecia Pharmaceuticals using its proprietary ZipDose additive manufacturing (3D printing) technology to produce porous tablets that disintegrate within seconds after the patient takes a sip of water. In addition, the company can produce customized doses containing 10 to 1000 milligrams of an active ingredient. The company expects to launch Spritam in the first quarter of 2016.

Accelerating drug development and approval


	Much discussion within and outside of the pharmaceutical industry in 2015 focused on the need to accelerate the drug development and approval process to provide effective solutions for not only thousands of rare conditions with no current treatments, but also for major diseases that remain unaddressed. This issue was, in fact, one of few that the divided US House of Representatives agreed on. The 21st Century Cures bill was passed overwhelmingly in the House with a 344–77 vote and was supported nearly equally by Democrats and Republicans. In addition to calling for a further $8.75 billion in funding for the National Institutes of Health, the bill outlines measures for accelerating all aspects of the drug development and approval process, such as patient-focused drug development, modern approaches to clinical trial design, increasing communication and information exchange, improving manufacturing efficiencies, and the introduction of more pathways for accelerated approval by FDA.

	There have, however, been questions raised about the increasing use of accelerated drug approval programs by FDA and the possible impact that such programs may have on the safety and efficacy of those drugs (10). The concern centers around the fact that accelerated approvals are often based on the results of smaller, early-phase trials with fewer patients and then expect manufacturers to develop additional post-market data. While these programs were initially intended for drugs that offered significant advances in treatment over existing drugs or new treatments for conditions that lacked any therapies, the majority of new drugs approved today are now associated with at least one of the four possible programs- fast track, accelerated approval, priority review, and orphan drug designation-with the result that many are likely not first-inclass or highly innovative (10).


	Of the 30 new molecular entities and biologic license applications approved by FDA through Oct. 27, 2015, 60% were NMEs and 14 (47%) had one or more accelerated approval designations. In line with the market data outlined above, the greatest numbers of new drug approvals were for oncology products and treatments related to cardiovascular diseases. Six drugs for the treatment of a variety of cancers (metastatic breast cancer), differentiated thyroid cancer, multiple myeloma, pediatric neuroblastoma, advanced local basal cell carcinoma (skin cancer), and advanced colorectal cancer were approved, three of which had one or more accelerated approval designations (11–16).

	Unituxin (dinutuximab) from United Therapeutics is an antibody that binds to the surface of neuroblastoma cells and is the first approval of a therapy aimed specifically at the treatment of patients with high-risk neuroblastoma (14). Farydak (panobinostat) from Novartis Pharmaceuticals is effective for the treatment of multiple myeloma, a form of blood cancer that primarily affects older adults, and is the first histone deacetylase (HDAC) inhibitor approved for this indication (13). Farydak is used in combination with the chemotherapy agent bortezomib and the anti-inflammatory medication dexamethasone and operates by a mechanism different from that of existing therapies, which earned it an accelerated review and priority review in addition to orphan drug status.

	Ibrance (palbociclib) from Pfizer for the treatment of advanced (metastatic) breast cancer earned a breakthrough therapy designation because preliminary clinical evidence suggested that the drug may offer a substantial improvement over available therapies (11). It works by inhibiting the cyclin-dependent kinases (CDKs) 4 and 6, which are known to promote the growth of cancer cells. Ibrance also received priority review and was approved under FDA’s accelerated approval program. A seventh drug, Varubi (rolapitant) from Tesaro, was also approved for the prevention of delayed phase chemotherapy- induced nausea and vomiting (17).

	The second largest category of approvals includes six drugs for the treatment of ailments associated with cardiovascular disease. Savaysa (edoxaban) from Daiichi Sankyo (18) and Kengreal (canegrelor) from The Medicines Company (19) are designed to prevent blood clots. Amgen’s Corlanor (ivabradine) (20) and Novartis’ Entresto (sacubitril/ valsartan) (21) are for the treatment of heart failure. Both received priority review and fast-track designation.

	Two drugs were also approved for the treatment of high cholesterol: Repatha (evolocumab) from Amgen (22) and Pratulent (alirocumab) from Sanofi-Aventis US and Regeneron Pharmaceuticals (23). These antibodies are the first members of a new class of injectable drugs known as PCSK9 inhibitors and work by preventing the PCSK9 protein from binding to receptors on the liver that remove LDL cholesterol from the blood.

	Schizophrenia patients can look forward to three new possible treatments that were approved in 2015: Vralyar (cariprazine) from Forest Laboratories (distributed by Actavis Pharma) (24), Aristada (aripiprazole lauroxil) from Alkermes (25), and Rexulti (brexpiprazole) from Otuska Pharmaceutical Company (26).

	The fifth and sixth antibiotics were also approved as Qualified Infectious Disease Products (QIDPs), a designation given to antibacterial or antifungal drug products that treat serious or lifethreatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. Cresemba (isavuconazonium sulfate) from Astellas Pharma is a new antifungal drug product used to treat adults with rare but serious invasive aspergillosis and invasive mucormycosis infections (27). Avycaz (ceftazidimeavibactam), distributed by Forest Pharmaceuticals, is a new antibacterial drug for the treatment of adults with complicated intra-abdominal and complicated urinary tract infections (28).

	Several first treatments were also approved:

		The breakthrough therapy Orkambi (lumacaftor 200 mg/ivacaf tor 125 mg) from Vertex Pharmaceuticals is the first drug approved for cystic fibrosis that treats the cause of the diseases in people with two copies of the F508del mutation (29).

		Xuriden (uridine triacetate) from Wellstat Therapeutics Corporation is the first FDA-approved treatment for patients with hereditary orotic aciduria, a rare metabolic disorder that has been reported in approximately 20 patients worldwide (30).

		Addyi (flibanserin) from Sprout Pharmaceuticals is the first treatment for acquired, generalized hypoactive (low) sexual desire disorder (HSDD) in premenopausal women, but was approved with a risk evaluation and mitigation strategy (REMS) including elements to assure safe use (ETASU) due to the increased risk of severe hypotension and syncope resulting from the interaction of Addyi with alcohol (31).

		Daklinza (daclatasvir) from Bristol- Myers Squibb is the first drug that has demonstrated safety and efficacy to treat chronic genotype 3 hepatitis C infections without the need for co-administration of interferon or ribavirin (32).

		Cholbam (cholic acid) capsules from Asklepion Pharmaceuticals is the first FDA-approved treatment for pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects and those with peroxisomal disorders (including Zellweger spectrum disorders). Cholbam is an oral treatment and was granted a rare pediatric disease priority review voucher-a provision that encourages the development of new drugs and biologics for the prevention and treatment of rare pediatric diseases (33).


	1. Transparency Market Research, “Global Active Pharmaceutical Ingredients (API) Market to Soar at 6.5% CAGR till 2020 Thanks to Rise in Abbreviated New Drug Applications (ANDAs),” Press Release, Oct. 1, 2015.
	2. Grandview Research, “High Potency Active Pharmaceutical Ingredients (HPAPI) Market Worth $25.86 Billion by 2022,” Press Release, Oct. 1, 2015
	3. FDA, “

New Molecular Entity and New Therapeutic Biological Product Approvals for 2015

,” accessed Oct. 27 2015.
	4. FDA, “FDA approves new drug to treat hyperkalemia,” Press Release, Oct. 21, 2015.
	5. FDA, “

New Molecular Entity and New Therapeutic Biological Product Approvals for 2014

,” accessed Oct. 27, 2015.
	6. FDA, “

,” accessed Oct. 27, 2015.
	7. Reportlinker, “Global Biosimilar Market Outlook 2020-Reportlinker Review,” Press Release, Oct. 29, 2015.
	8. FDA, “FDA approves first biosimilar product Zarxio,” Press Release, March 6, 2015.
	9. Aprecia Pharmaceuticals, “FDA Approves the First 3D Printed Drug Product”, Press Release, Aug. 3, 2015.
	10. A.S. Kesselheim et al. 

, September 2015 DOI: 10.1136/bmj.h4633.
	11. FDA, “FDA approves Ibrance for postmenopausal women with advanced breast cancer,” Press Release, Feb. 3, 2015.
	12. FDA, “FDA approves Lenvima for a type of thyroid cancer,” Press Release, Feb. 13, 2015.
	13. FDA, “FDA approves Farydak for treatment of multiple myeloma,” Press Release, Feb. 23, 2015.
	14. FDA, “FDA approves first therapy for high-risk neuroblastoma,” Press Release, March 10, 2015.
	15. FDA, “FDA approves new treatment for most common form of advanced skin cancer,” Press Release, July 24, 2015.
	16. FDA, “FDA approves new oral medication to treat patients with advanced colorectal cancer,” Press Release, Sept. 22, 2015.
	17. FDA, “FDA approves new drug treatment for nausea and vomiting from chemotherapy,” Press Release, Sept. 2, 2015.
	18. FDA,” FDA approves anti-clotting drug Savaysa,” Press Release, Jan. 8, 2015.
	19. FDA, “FDA approves new antiplatelet drug used during heart procedure,” Press Release, June 22, 2015.
	20. FDA, “FDA approves Corlanor to treat heart failure,” Press Release, April 15, 2015.
	21. FDA, “FDA approves new drug to treat heart failure,” Press Release, July 7, 2015.
	22. FDA, “FDA approves Repatha to treat certain patients with high cholesterol,” Press Release, Aug. 27, 2015.
	23. FDA, “FDA approves Praluent to treat certain patients with high cholesterol,” Press Release, July 24, 2015.
	24. FDA, “FDA approves new drug to treat schizophrenia and bipolar disorder,” Press Release, Sept. 17, 2015.
	25. FDA, “FDA approves new injectable drug to treat schizophrenia,” Press Release, Oct. 6, 2015.
	26. FDA, “FDA approves new drug to treat schizophrenia and as an add on to an antidepressant to treat major depressive disorder,” Press Release, July 13, 2015.
	27. FDA, “FDA approves new antifungal drug Cresemba,” Press Release, March 6, 2015.
	28. FDA, “FDA approves new antibacterial drug Avycaz”, Press release, Feb. 25, 2015.
	29. FDA, “FDA approves new treatment for cystic fibrosis,” Press Release, July 2, 2015.
	30. FDA, “FDA approves new orphan drug to treat rare autosomal recessive disorder,” Press Release, Sept. 4, 2015.
	31. FDA, “FDA approves first treatment for sexual desire disorder,” Press Release, Aug. 18, 2015.
	32. FDA, “FDA approves new treatment for chronic hepatitis C genotype 3 infections,” Press Release, July 24, 2015.
	33. FDA, “FDA approves Cholbam to treat rare bile acid synthesis disorders,” Press Release, March 17, 2015.

: 
	When referring to this article, please cite it as C. Challener, “Outlook Bright for Branded and Generic Active Ingredients,” 

A strong API market is expected in 2016 despite fewer new drug approvals.

Outlook Bright for Branded and Generic Active Ingredients

	The structural complexity of newer small-molecule drug candidates is increasing, with many containing several different heterocyclic substructures and numerous stereogenic centers. Preparing single isomers of these compounds can be quite challenging and requires the use of atom-efficient, low-waste, regio- and stereoselective reactions, according to Dave Green, vice-president of R&D with ANGUS Chemical Company. “A considerable amount of effort is being consumed to expand the utility of classic synthetic methods, often focusing on enantioselective catalysis or combining steps into what are now being called multi-component reactions (MCRs),” he observes.

	In particular, multi-component coupling reactions for the generation of heterocycles in fewer steps with high regioselectivity and reduced processing times, cost, and waste are attracting significant interest. A new cross-dehydrogenative, heteroaromatic carbon–hydrogen (C–H) silylation reaction catalyzed by the simple base potassium tert-butoxide (KOtBu) is also a potentially useful reaction for API synthesis.

	Older methods for the synthesis of heterocycles typically relied on the stepwise construction of linear frameworks followed by final cyclizations. “Today,” says Green, “reaction conditions and catalytic methods are being developed such that three or even four reactive components can be simultaneously combined, resulting in a cascade that leads to a highly functionalized product.” Nitroalkanes are often one of the building blocks used for the synthesis of nitrogen-containing heterocycles.

	In one example published by Maiti et al. in 2010 (1), fully substituted pyrroles were prepared with five independently selected substituents (four-component reaction) in a completely regioselective manner. “It is also notable that all of the starting materials used in the reaction are readily accessible monofunctional reagents,” Green notes. For reactions using nitromethane, isolated yields were often in the 70 to 80% range, and typically higher than those using nitroethane (1). The 3-ketopyrroles obtained from the reaction are highly versatile intermediates and can be used for a variety of synthetic applications, according to Green.

	Dehaen and co-workers reported a three-component coupling reaction between nitroalkanes, alkyl azides, and aldehydes that affords tri-substituted triazoles, again in a regioselective manner (2). This reaction proceeds via 1,3-dipolar cycloaddition of the azide with a nitroalkene formed 

. Tazobactam is one example of a current API that contains a 1,2,3-triazole moiety.

	ANGUS utilized MCR technology to synthesize 3-(N-methyl)-1-phenyl-1-propanol via a heterocyclic intermediate. The three-component reaction of formaldehyde and styrene with N-methyl hydroxylamine, which was readily prepared by selectively reducing nitromethane, proceeded through an isoxazolidine intermediate that was ring-opened to give only the desired regioisomer in nearly quantitative yield. This direct route to 3-(N-methyl)-1-phenyl-1-propanol is an important development, because this compound is the key intermediate in the manufacture of fluoxetine, according to Green. “By using the MCR technique, isolation of the methyl nitrone intermediate was avoided, preventing the issues associated with its propensity to oligomerize,” he explains.

	One of the challenges when preparing nitrogen-containing heterocycles via multi-component reactions that require the use of nitromethane or compounds like N-methylhydroxylamine (MHA) is the reactivity of these substances. Nitromethane, azides, and to a lesser extent MHA are energetic materials, and special handling requirements must be considered. “Minimization of the quantities of in-process and/or isolated materials is an excellent way to also minimize the potential energy release at any given point in the process,” Green says. He points to the recent development of commercially available micro-flow reactors as providing both laboratory- and production-scale options. “At the lab scale, a variety of process conditions and stoichiometries can be evaluated in order to define the safe operating limits for reagent concentrations/ temperature/pressure with essentially no potential energy release risk. In turn, scaling the best operating conditions in an analogous configuration greatly minimizes the risk associated with handling the larger volumes needed for commercial production,” he observes. 

	The substitution of carbon for fluorine is recognized as an attractive method for preparing drug candidates with improved lipophilicity and other attractive properties. More recently, compounds containing silicon-carbon bonds have attracted interest, because such derivatives are also often more stable and have improved solubilities and pharmacokinetic properties.

	To date, heteroaromatic organosilanes have been prepared using two rather limited methods: stoichiometric reaction of a heteroaromatic organometallic intermediate generated via a Grignard reaction with a silicon electrophile and catalytic C–H silylation mediated by a rhodium or iridium catalyst in the presence of an excess of a hydrogen acceptor. The functional group tolerance of these methods is minimal. In addition, they require the use of large quantities of reactive and/or expensive reagents. As a consequence, there is a desire for more general routes to organosilanes that are not only more cost-effective and practical on an industrial scale, but also provide access to novel compounds.

	
	Students in the Grubbs and Stoltz groups at the California Institute of Technology recently stumbled on an interesting reaction catalyzed by KOtBu. They were investigating the conversion of biomass to chemicals via the breakage of carbon-oxygen bonds using an iron catalyst, potassium tert-butoxide, and a hydrosilane as a hydride equivalent and observed that a control reaction with just KOtBu and the hydrosilane gave silylated heteroaromatics as byproducts (4).

	Using 1-methylindole as a model substrate, the reaction conditions were optimized for the selective production of a single organosilane in high yield. A catalytic amount (1-20 mol%) of KOtBu was found to be most effective, and cross dehydrogenative heteroaromatic C–H silylation occurs without the need for an acceptor, resulting in the generation of hydrogen gas as the only byproduct. Extensive studies were also performed to confirm that the KOtBu was indeed the catalyst (3).

	The reaction is noteworthy not only because it is novel, but also because of its scope, scalability, and the fact that it is catalyzed by an inexpensive, commercially available substance based on potassium, which is an abundant alkali metal and not a rare and expensive precious metal. Furthermore, the reaction proceeds under mild conditions, has no complicated byproducts, the product is readily isolated, and in many cases no solvent is required.

	With respect to the scope of the reaction, indoles with a variety of substituents on the nitrogen (N) molecule and at various positions on the arene ring, and many different electron-neutral and electron-rich N-, oxygen- and sulfur-containing heterocyclic compounds are tolerated, although carbonyl groups generally are not unless protected as acetals. In addition, bromide, iodide, cyano, and nitro substituents inhibit the reaction, while fluoride, chloride, trifluoromethyl, epoxide, N-alkyl aziridine, pyridine, and tertiary amine and phosphine groups do not (3).

	Simple arenes also undergo the dehydrogenative heteroaromatic C–H silylation reaction, but the reactivity depends on the substituents. Anisole affords the ortho-substituted silylated product, while toluene and similar compounds undergo directing-group-free C(sp3)–H silylation to generate silylated benzyl derivatives. The electronic nature of any oxygen substituents also determines the regioselectivity (on the ring or the substituent) of the silylation (3).

	Importantly for pharmaceutical applications, the reaction appears to be readily scalable; the neat reaction of N-methyl indole with 1.5 equivalents of triethylsilane at 45 °C was performed on a 100-gram scale followed by simple filtration and distillation, affording the desired C2 silylated product in 76% yield with high regioselectivity (> 20:1) (3).

	In addition, the facile silylation of APIs was achieved to demonstrate the potential for application of the reaction for late-stage modification of pharmaceutically relevant compounds. The antihistamine thenalidine and the antiplatelet drug ticlopidine were successfully subjected to the regioselective C–H silylation reaction (58–68% yield with high chemo- and regioselectivity) (3). Therefore, this method should be useful for the rapid synthesis of compound libraries. Different heteroarylsilanes obtained using the KOtBu chemistry were also converted to more complex molecules via silicon-directed Suzuki–Miyaura cross-coupling and Hiyama–Denmark cross-coupling reactions to demonstrate their synthetic utility (3).

Multi-component coupling reactions for the generation of heterocycles in fewer steps reduced processing times, cost, and waste are attracting interest.

Researchers Identify Advances for Heterocyclic Chemistry

Fluorine atoms have a unique combination of electronic and physical properties. As such, when incorporated into APIs, fluorine atoms often influence their protein binding affinity and lipophilicity. Fluorination can thus significantly impact the bioavailability of drug substances. “Fluorination is a key reaction in organic synthesis, as evidenced by the fact that between 15% to 20% of all medicines and agrochemicals on the market contain at least one fluorine atom in their structure, where fluorine is used to modify properties of the drugs like lipophilicity and bioavailability or metabolic stability,” states Rafael Antunes, director of API portfolio development with Hovione.

	Traditional and cost-effective fluorinating reagents are corrosive and often toxic and, therefore, require special handling and equipment. In addition, they cannot be used with intermediates containing other sensitive functionality. Thus, the synthesis of organic fluoro-compounds is not trivial at industrial scale--it requires special equipment, materials of construction, reaction conditions (sometimes cryogenic), and controls to tackle the difficulty in safely handling and disposing of fluorinating reagents, according to Antunes. “Reaction control is a fundamental aspect. The low selectivity (chemo-, regio-, and/or stereo-) of the reactions, the low stability of some fluorine-containing species, together with hazardous sampling and sample handling impose a heavy burden for the synthesis of fluorochemicals,” he adds.

	The search for safer, easy-to-handle, inexpensive, and selective fluorinating reagents has been underway for decades and continues today. Most recently, solid reagents are showing promise, at least for use by medicinal chemists. Even more promising are coupling reactions that allow the incorporation of fluorinated synthons through carbon-carbon rather than carbon-fluorine bond formation.


	Several solid fluorinating reagents have been introduced to the market. One example that has recently been attracting more interest is XtalFluor-E from Manchester Organics (developed in partnership with OmegaChem). (Diethylamino)difluorosulfonium tetrafluoroborate is an easily handled crystalline solid with enhanced thermal stability when compared to other reagents in this class, including a higher decomposition temperature with lower exothermic heat and higher onset temperature for self-accelerated decomposition (1), according to Dave Tovell, director of Manchester Organics. In addition, it does not generate free hydrogen fluoride (HF) and thus is usually compatible with glass equipment. The partnership has also demonstrated that this fluorinating reagent typically produces fewer elimination side products, and thus greater selectivity, than more traditional nucleophilic fluorinating reagents.

	With their attractive physical, reactivity, and health and safety profiles, these newer reagents are finding growing use at the discovery and early process phases of drug development. They do, however, carry a relatively higher cost than traditional fluorinating reagents (HF, potassium fluoride [KF] and fluorine gas [F

]) and thus are generally less economical for use on the commercial-scale.

Organometallic coupling reactions are most exciting


	Newer difluormethylation and trifluoromethylation chemistry, which involves the formation of carbon-carbon bonds rather than direct fluorination, is one of the most exciting developments in organofluorine chemistry in recent years, according to Tovell. “These reactions occur under mild conditions and often tolerate many different functional groups,” he notes.

	Hartwig’s trifluoromethyl(1,10-phenanthroline)copper ((Phen)Cu-CF3) reagent is an easily handled, thermally stable, single-component reagent for the trifluoromethylation of both electron-rich and electron-deficient aryl and vinyl iodides, including sterically-hindered iodoarenes, in high yields under mild conditions (2). Notably, aldehyde, nitroarene, ketone, and ester functionalities are tolerated. The reagent is sold under the trade name Trifluoromethylator by Catylix and is commercially available through Aldrich Chemical.

	Shibata developed a method for the electrophilic α-trifluoromethylation of β-ketoesters using the fluorinated Johnson reagent [(oxido)phenyl(trifluoromethyl)-λ

-sulfanylidene]dimethylammonium tetrafluoroborate (3). Meanwhile, hypervalent iodine(III)-CF

 reagents developed by Togni are widely used for the trifluoromethylation of thiols, alcohols, phosphines, and heteroarenes (4-8). The radical trifluoromethylation of heteroarenes using the Langlois reagent (sodium trifluoromethanesulfinate) or zinc(II) bis(trifluoromethanesulfinate) (Zn(SO2CF3)2) with tert-butyl hydroperoxide have also been achieved by Baran (9-11).

	Zinc difluoromethanesulfinate (DFMS), also developed by the Baran group (11), allows for the simple difluoromethylation of a wide range of heteroaromatic substrates in air. Nucleophilic difluoromethylation of carbonyls and imines can be achieved using (difluoromethyl)trimethylsilane (12), a reagent developed by Hu and coworkers.

	There are numerous other research groups developing selective and high-yielding nucleophilic and electrophilic difluoromethylation and trifluoromethylation strategies for substrates ranging from carbonyl compounds to alkenes. “These new techniques for the selective incorporation of fluorine atoms into complex organic molecules under mild conditions are very exciting advances for API synthesis. The pharmaceutical industry is under increasing pressure to reduce costs, and any new technologies that can improve route efficiencies and yields and do so cost effectively will attract significant attention,” asserts Tovell. He adds that it is still early days with respect to the development of these types of chemistry and he expects further improvements in the coming years.

Organometal-catalyzed direct fluorination also of interest


	Organometallic catalysts have also been applied to the direct fluorination of a variety of substrates. Two examples include Buchwald’s method for the nucleophilic fluorination of aryl triflates with cesium or potassium fluoride (13) and Ritter’s silver-catalyzed fluorination reaction in which aryl stannanes are converted to fluorides using silver triflate as the catalyst and F-TEDA-PF6, which is an anion-exchange product of Selectfluor (chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); F-TEDA-BF4) as the fluoride source (14).

	Antunes adds that the development of Selectfluor by Eric Banks (marketed by Air Products) is the most important ‘recent’ development. This reagent has transformed the production of fluorinated pharmaceuticals, with 134 patents published that cite Selectfluor, and approximately 80% of all fluorinated steroids produced using the agent. “This reagent bypasses hazardous fluorine processing steps and makes the production of drugs containing fluorine much cheaper and safer. Every year, around 25 tonnes (worth $7.5 million) of Selectfluor are used in the industry, making it the most commonly used electrophilic fluorinating agent in pharmaceutical manufacturing,” he notes.

Exploring the potential of flow chemistry


	The benefits of flow chemistry include reduced operating costs, a lower footprint, decreased capital expenditures combined with improved process efficiencies, control, and product quality, and the ability to perform chemical reactions that are not feasible or present significant hazards in batch operations. As a result, there is great interest in this technology for the synthesis of pharmaceutical intermediates and APIs.

	Not surprisingly, flow chemistry is a natural fit with fluorination reactions, particularly those involving conventional toxic and corrosive reagents. “Minimizing the quantity of reagents that are needed at any one time not only reduces the hazards associated with these reactions, but also allows for optimization of yields and selectivities,” Tovell explains. There are generally high expectations for flow chemistry to overcome many of the challenges of traditional fluorination reactions (the need for special equipment, to handle hazardous chemistries, and run strictly controlled reactions) due to more efficient mass and energy transfers, short residence times, and moisture free-operating conditions, agrees Antunes.

	These benefits shouldn’t be limited just to traditional fluorination chemistry, however. “Combination of flow chemistry with the newer difluoromethylation and trifluoromethylation techniques has the potential to provide low-cost, highly effective routes to complex fluorinated molecules,” says Tovell.

	Manchester Organics will be investigating the application of a continuous-flow approach to various fluorination strategies over the next few years. One of the challenges involves optimizing the conditions for reactions that require the use of solid reagents. There are numerous parameters to consider, such as the dilution factor, solvent choice, and reaction temperature. “There is a lot of work to be done, but we believe that this approach will enable the development of effective solutions for many of our customers that are looking for improved methods for the production of their fluorinated compounds,” Tovell observes.


	Since the first introduction of reagents with improved handling and toxicity profiles, such as (2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor), Selectfluor, and diethylaminosulfur trifluoride (DAST), there has been an explosion in the development of new fluorination methods.

	Access to solid reagents such as XtalFluor-E and FLUOLEAD from UBE Industries has led to even further advances in fluorination chemistry, with the number of literature reports on new techniques growing exponentially, according to Tovell. Studies of the reactivities of these various reagents combined with new data obtained using state-of-the-art analytical and modeling technologies are enabling researchers to gain a better understanding of the interactions of fluorine with other atoms in different molecular settings. Tovell believes that this new knowledge will lead to the development of even more effective fluorinating reagents that are highly selective (chemo-, regio-, and stereo), safer to use, can tolerate a wider range of functional groups, are environmentally acceptable, and can be produced at a cost level that will facilitate their use in commercial drug manufacturing.

. 75(10), 3401-3411 (2010).
	2. J.F. Hartwig et al., 

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	3. N. Shibata et al., 

. 20, 3465-3468 (2008).
	4. A. Togni et al., 

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	5. A. Togni et al., A

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	6. A. Togni et al., 

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	7. A. Togni et al., 

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	8. A. Togni et al., 

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	9. P.S. Baran et al., 

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	10. P.S. Baran et al., 

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	11. P.S. Baran et al., 

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	12. J. Hu et al., 

13(19), 5342-5345 (2011).
	13. S. Buchwald et al.,

 325(5948), 1661-1664 (2009).
	14. T. Ritter et al., 

In the ongoing search for better fluorinating reagents, solid reagents and new coupling reactions are showing promise.

New Reagents and Reactions Advance Fluorination Chemistry

Efficient syntheses are possible using multi-component and cross-dehydrogenative, heteroaromatic C–H silylation reactions

Advances in Heterocyclic Chemistry for API Synthesis

The structural complexity of newer small-molecule drug candidates is increasing, with many containing several different heterocyclic substructures and numerous stereogenic centers. Preparing single isomers of these compounds can be quite challenging and requires the use of atom-efficient, low-waste, regio-, and stereoselective reactions, according to Dave Green, vice-president of R&D with ANGUS Chemical Company. “A considerable amount of effort is being consumed to expand the utility of classic synthetic methods, often focusing on enantioselective catalysis or combining steps into what are now being called multi-component reactions (MCRs),” he observes.

	In particular, multi-component coupling reactions for the generation of heterocycles in fewer steps with high regioselectivity and reduced processing times, cost, and waste are attracting significant interest. A new cross-dehydrogenative, heteroaromatic carbon-hydrogen (C-H) silylation reaction catalyzed by the simple base potassium tert-butoxide (KOtBu) is also a potentially useful reaction for API synthesis.


	Older methods for the synthesis of heterocycles typically relied on the stepwise construction of linear frameworks followed by final cyclizations. “Today,” says Green, “reaction conditions and catalytic methods are being developed such that three or even four reactive components can be simultaneously combined, resulting in a cascade that leads to a highly functionalized product.” Nitroalkanes are often one of the building blocks used for the synthesis of nitrogen-containing heterocycles.


	In one example published by Maiti et al. in 2010 (1), fully substituted pyrroles were prepared with five independently selected substituents (four-component reaction) in a completely regioselective manner. “It is also notable that all of the starting materials used in the reaction are readily accessible monofunctional reagents,” Green notes. For reactions using nitromethane, isolated yields were often in the 70 to 80% range, and typically higher than those using nitroethane (1). The 3-ketopyrroles obtained from the reaction are highly versatile intermediates and can be used for a variety of synthetic applications, according to Green.

. Tazobactam is one example of a current API that contains a 1,2,3-triazole moiety.


	ANGUS utilized MCR technology to synthesize 3-(N-methyl)-1-phenyl-1-propanol via a heterocyclic intermediate. The three-component reaction of formaldehyde and styrene with N-methyl hydroxylamine, which was readily prepared by selectively reducing nitromethane, proceeded through an isoxazolidine intermediate that was ring-opened to give only the desired regioisomer in nearly quantitative yield. This direct route to 3-(N-methyl)-1-phenyl-1-propanol is an important development, because this compound is the key intermediate in the manufacture of fluoxetine, according to Green. “By using the MCR technique, isolation of the methyl nitrone intermediate was avoided, preventing the issues associated with its propensity to oligomerize,” he explains.


	One of the challenges when preparing nitrogen-containing heterocycles via multi-component reactions that require the use of nitromethane or compounds like N-methylhydroxylamine (MHA) is the reactivity of these substances. Nitromethane, azides, and to a lesser extent MHA are energetic materials, and special handling requirements must be considered. “Minimization of the quantities of in-process and/or isolated materials is an excellent way to also minimize the potential energy release at any given point in the process,” Green says. He points to the recent development of commercially available micro-flow reactors as providing both laboratory- and production-scale options. “At the lab scale, a variety of process conditions and stoichiometries can be evaluated in order to define the safe operating limits for reagent concentrations/temperature/pressure with essentially no potential energy release risk. In turn, scaling the best operating conditions in an analogous configuration greatly minimizes the risk associated with handling the larger volumes needed for commercial production,” he observes. 


	The substitution of carbon for fluorine is recognized as an attractive method for preparing drug candidates with improved lipophilicity and other attractive properties. More recently, compounds containing silicon-carbon bonds have attracted interest, because such derivatives are also often more stable and have improved solubilities and pharmacokinetic properties.

	To date, heteroaromatic organosilanes have been prepared using two rather limited methods: stoichiometric reaction of a heteroaromatic organometallic intermediate generated via a Grignard reaction with a silicon electrophile and catalytic C-H silylation mediated by a rhodium or iridium catalyst in the presence of an excess of a hydrogen acceptor. The functional group tolerance of these methods is minimal. In addition, they require the use of large quantities of reactive and/or expensive reagents. As a consequence, there is a desire for more general routes to organosilanes that are not only more cost-effective and practical on an industrial scale, but also provide access to novel compounds.


	Students in the Grubbs and Stoltz groups at the California Institute of Technology recently stumbled on an interesting reaction catalyzed by KOtBu. They were investigating the conversion of biomass to chemicals via the breakage of carbon-oxygen bonds using an iron catalyst, potassium tert-butoxide, and a hydrosilane as a hydride equivalent and observed that a control reaction with just KOtBu and the hydrosilane gave silylated heteroaromatics as byproducts (3).

	Using 1-methylindole as a model substrate, the reaction conditions were optimized for the selective production of a single organosilane in high yield. A catalytic amount (1-20 mol%) of KOtBu was found to be most effective, and cross dehydrogenative heteroaromatic C-H silylation occurs without the need for an acceptor, resulting in the generation of hydrogen gas as the only byproduct. Extensive studies were also performed to confirm that the KOtBu was indeed the catalyst (3).

	Simple arenes also undergo the dehydrogenative heteroaromatic C-H silylation reaction, but the reactivity depends on the substituents. Anisole affords the ortho-substituted silylated product, while toluene and similar compounds undergo directing-group-free C(sp3)-H silylation to generate silylated benzyl derivatives. The electronic nature of any oxygen substituents also determines the regioselectivity (on the ring or the substituent) of the silylation (3).

	In addition, the facile silylation of APIs was achieved to demonstrate the potential for application of the reaction for late-stage modification of pharmaceutically relevant compounds. The antihistamine thenalidine and the antiplatelet drug ticlopidine were successfully subjected to the regioselective C-H silylation reaction (58-68% yield with high chemo- and regioselectivity) (3). Therefore, this method should be useful for the rapid synthesis of compound libraries. Different heteroarylsilanes obtained using the KOtBu chemistry were also converted to more complex molecules via silicon-directed Suzuki-Miyaura cross-coupling and Hiyama-Denmark cross-coupling reactions to demonstrate their synthetic utility (3).

. 75(5), 1674-1683 (2010).
	2. W. Dehaen et al., Angew. 

. 53(38), 10155-10159 (2014).
	3. A. A. Toutov et al., 

: 
	When referring to this article, please cite it as C. Challener, “Advances in Heterocyclic Chemistry for API Synthesis,” 

Efficient syntheses are possible using multi-component and cross-dehydrogenative, heteroaromatic C-H silylation reactions.