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

Cynthia A. Challener

Following two years of near-record numbers of new drug approvals by FDA, with 41 in 2014 (1) and 45 in 2015 (2), 2016 appears to be seriously bucking the trend, with only 20 approvals issued as of Dec. 14, 2016 (3). The sharp decline was not expected. What might be the reasons? John Jenkins, director of FDA’s Office of New Drugs, attributed the difference to a decline in the number of submitted applications, more complete response letters in 2016, and the fact that five approvals originally scheduled for 2016 were finalized earlier in 2015 (4). On a positive note, Jenkins reported that the number of applications received by FDA through Dec. 9, 2016 was 36, surpassing the average number (35) of new molecular entity filings for the past decade.

	Notably, the decline in approvals does not seem to be having an impact on growth expectations for the global API market. Mordor Intelligence projects the global API market to expand at a compound annual growth rate of 6.5% from $154 billion in 2015 to $225 billion in 2021 (5).

	While chemical compounds continue to account for the greatest percentage of APIs, biologic drug substances are growing at the fastest rate. APIs were intended slightly more often for branded drugs compared to generic drugs (43.5%) in 2015, and APIs for cancer treatments are experiencing the fastest growth vs. APIs for other therapies. North America remains the largest market for APIs, but demand is growing most rapidly in Asia-Pacific (5).

	The 20 approvals in 2016 included treatments for asthma, type II diabetes, different cancers, hepatitis C, plaque psoriasis, multiple sclerosis, muscular dystrophy, and several rare diseases. Eight of the approvals were for biologics, including seven monoclonal antibodies (mAbs) and one hormone. Two were radioactive diagnostics agents and two were for the treatment of hepatitis C. Merck, Eli Lilly, and Sanofi each received two approvals. Half of the new drugs approved by FDA in 2016 received one or more special designations. Three are considered new classes of drugs, and three are the first-ever treatments for the diseases they target.

	With passage of the FDA Safety and Innovation Act (FDASIA) in 2012, FDA was granted authority to implement expedited review and approval programs to accelerate the introduction of novel medications to the market. Four programs are currently in use. Manufacturers can qualify for fast track and breakthrough therapy designations, and accelerated approval and priority review processes depending on the characteristics of their drug candidates. Breakthrough therapies provide substantial improvement over currently available treatments. Fast Track drugs meet unmet medical needs and treat serious conditions. Accelerated approval is available for similar reasons. Priority review is granted to drugs that have improved safety and effectiveness compared to current medicines.

	Drug companies are utilizing these pathways. In 2014 and 2015, respectively, 66% and 60% of the 41 and 45 new drugs approved by FDA received one or more special designation or was granted an expedited review of some kind (6,7).

	In 2016, five of the newly approved drugs were awarded the breakthrough therapy designation, three received fast track status, five received accelerated approval, and eight underwent priority review. In addition, six of the newly approved treatments were classified as orphan drugs. One product-Exondys 51 (eteplirsen, Sarepta Therapeutics) for the treatment of patients with Duchenne muscular dystrophy (DMD)-received priority review for a rare pediatric disease. Notably, two of the approved drugs in 2016 had a total of five special designations (8).

	Several of the newly approved drugs are the first new therapies approved by FDA for the treatment of different diseases. Exondys 51 is the first drug approved to treat patients with DMD that have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13% of the population with DMD (8).

	In addition to receiving the seventh rare pediatric disease priority review voucher issued by FDA since the program began, Exondys 51 was granted fast track and orphan drug designations and was approved under the accelerated approval pathway based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. FDA is requiring Sarepta Therapeutics to conduct a clinical trial to confirm the drug’s clinical benefit.

	Nuplazid (pimavanserin) from Acadia Pharmaceuticals is the first drug approved to treat hallucinations and delusions associated with psychosis experienced by as many as 50% of people with Parkinson’s disease. An estimated 50,000 Americans are diagnosed with Parkinson’s disease each year, according to the National Institutes of Health, and about 1 million Americans have the condition. Nuplazid received priorty review and was designated a breakthrough therapy (9).

	Defitelio (defibrotide sodium) marketed by Jazz Pharmaceuticals is the first FDA-approved therapy for the treatment of severe hepatic veno-occlusive disease (VOD), a rare and life-threatening liver condition that can occur in adults and children that receive a stem cell transplant from blood or bone marrow (hematopoietic stem cell transplantation or HSCT). Fewer than 2% of patients develop severe hepatic VOD after HSCT, but as many as 80% of patients who develop severe hepatic VOD do not survive. Defitelio was granted priority review and designated an orphan drug (10).

	Epclusa (fixed dose combination of sofosbuvir and velpatasvir) from Gilead Sciences is the first regimen to treat all six major hepatitis C virus (HCV) genotypes and was approved for adult patients with chronic HCV. Velpatasvir is the new drug; sofosbuvir was approved in 2013. Epclusa was granted priority review (11).

	Lartruvo from Eli Lilly is the first new therapy approved by the agency for the initial treatment of soft-tissue sarcomas (STS), cancers that develop in muscles, fat, tendons or other soft tissues and cannot be cured with radiation or surgery, since doxorubicin’s approval more than 40 years ago. This platelet-derived growth factor (PDGF) receptor-alpha blocking antibody blocks PDGF receptors that cause tumor growth. The National Cancer Institute estimates that 12,310 new cases of STS and nearly 5000 deaths are likely to occur from the disease in 2016. Lartruvo (olaratumab) with chemotherapy drug doxorubicin was granted accelerated approval and priority review, as well as fast track, breakthrough therapy, and orphan designations (12).

	Other drugs approved in 2016 fall into new classes of compounds that act by new pathways. Genentech’s Tecentriq (atezolizumab) is the first FDA-approved PD-L1 inhibitor and the latest in the broader class of PD-1/PD-L1 targeted biologics approved by FDA in the past two years. This mAb was approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma, the most common type of bladder cancer.  It blocks PD-1/PD-L1 interactions between the body’s immune cells and some cancer cells, potentially helping the body’s immune system to fight cancer cells. Tecentriq received priority review and accelerated approval and was designated a breakthrough therapy (13).

	Venclexta (venetoclax) from AbbVie is the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell growth. The drug is for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a chromosomal abnormality called 17p deletion and who have been treated with at least one prior therapy. According to the National Cancer Institute, CLL is one of the most common types of leukemia in adults, with approximately 15,000 new cases diagnosed each year. The relevant chromosomal abnormality occurs in approximately 10% of patients with untreated CLL and in approximately 20% of patients with relapsed CLL. Venclexta was granted priority review and accelerated approval and designated a breakthrough therapy and orphan drug (14).

	Netspot from Advanced Accelerator Applications USA is the first kit for the preparation of gallium Ga 68 dotatate injection, a radioactive diagnostic agent for positron emission tomography imaging. The radioactive probe helps locate tumors in adult and pediatric patients with the rare condition somatostatin receptor positive neuroendocrine tumors by binding to receptors on the tumors, which develop in the hormone-producing cells of the body’s neuroendocrine system. Netspot received priority review and was designated an orphan drug (15).

	Several of the approved drugs in 2016 are intended for the treatment of diseases with existing therapies, but in some cases the new drug is of particular interest. For instance, Ocaliva (obeticholic acid) from Intercept Pharmaceuticals is only the second drug approved to treat patients with primary biliary cholangitis. Ursodeoxycholic acid, the only other approved drug, is effective in just over 50% of patients on its own and is not tolerated by many. An oral drug, Ocaliva binds to the farnesoid X receptor, a receptor found in the nucleus of cells in the liver and intestine, reducing bile flow from the liver and suppressing bile acid production in the liver. It received accelerated approval and fast track and orphan drug designations (16).

	Merck’s ZINPLAVA (bezlotoxumab) is approved for the reduction of the recurrence of Clos

 infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment for CDI and are at high risk for CDI recurrence. CDI is caused by bacteria that produce toxins, including toxin B. Developed by researchers at the University of Massachusetts Medical School’s MassBiologics Laboratory in conjunction with Medarex (now part of Bristol-Myers Squibb) and licensed to Merck in 2009, Zinplava, a human monoclonal antibody, binds to 

 toxin B and neutralizes its effects (17).

	Developed by Elusys Therapeutics in cooperation with the US Dept. of Health and Human Services’ Biomedical Advanced Research and Development Authority, Anthim (obiltoxaximab) is a mAb that neutralizes toxins produced by 

 and was approved for the treatment of inhalational anthrax in combination with appropriate antibacterial drugs. Inhalational anthrax is a rare disease that can occur after exposure to infected animals or contaminated animal products, or as a result of an intentional release of anthrax spores. Notably, the drug was approved under  FDA’s Animal Rule, which allows efficacy findings from adequate and well-controlled animal studies to support FDA approval when it is not feasible or ethical to conduct efficacy trials in humans (18).

	It is also worth noting that FDA’s Center for Drug Evaluation and Research (CDER) approved 72 “first generic drugs” in 2016 as of Nov. 16, 2016 (19). “First generics” are the first approval by FDA that permits a manufacturer to market a generic drug product in the United States and receive prioritized review.

New Molecular Entity and New Therapeutic Biological Product Approvals for 2014

New Molecular Entity and New Therapeutic Biological Product Approvals for 2015

New Molecular Entity and New Therapeutic Biological Product Approvals for 2016

,  accessed Dec. 14, 2016.
	4. J. Jenkins, “

,” presentation at FDA/CMS Summit, Dec. 14, 2016, accessed Dec. 14, 2016.
	5. Mordor Intelligence, “

Global Active Pharmaceutical Ingredients Market-Growth, Trends & Forecasts (2016-2021),

” September 2016, accessed Dec. 14, 2016.
	6. FDA,  

. January 2015, accessed Dec. 14, 2016.
	7. FDA, 

. January 2016, accessed Dec. 14, 2016.
	8. FDA, “FDA Grants Accelerated Approval to First Drug for Duchenne Muscular Dystrophy,” Press Release (Silver Spring, MD, Sept. 19, 2016).
	9. FDA, “FDA Approves First Drug to Treat Hallucinations and Delusions Associated with Parkinson’s disease,” Press Release (Silver Spring, MD, April 29, 2016).
	10. FDA, “FDA Approves First Treatment for Rare Disease in Patients Who Receive Stem Cell Transplant from Blood or Bone Marrow,” Press Release (Silver Spring, MD, March 30, 2016).
	11. FDA, “FDA Approves Epclusa for Treatment of Chronic Hepatitis C Virus Infection,” Press Release (Silver Spring, MD, June 28, 2016).
	12. FDA, “FDA Grants Accelerated Approval to New Treatment for Advanced Soft Tissue Sarcoma,” Press Release (Silver Spring, MD, Oct. 19, 2016).
	13. FDA, “FDA Approves New, Targeted Treatment for Bladder Cancer,” Press Release (Silver Spring, MD, May 18, 2016).
	14. FDA, “FDA Approves New Drug for Chronic Lymphocytic Leukemia in Patients with a Specific Chromosomal Abnormality,” Press Release, April 11, 2016.
	15. FDA, “FDA Approves New Diagnostic Imaging Agent to Detect Rare Neuroendocrine Tumors,” Press Release, (Silver Spring, MD, June 1, 2016).
	16. FDA, “FDA Approves Ocaliva for Rare, Chronic Liver Disease,” Press Release (Silver Spring, MD, May 31, 2016).
	17. Merck & Co., “FDA Approves Merck’s ZINPLAVA (bezlotoxumab) to Reduce Recurrence of Clost

Infection (CDI) in Adult Patients Receiving Antibacterial Drug Treatment for CDI Who Are at High Risk of CDI Recurrence,” Press Release (Silver Spring, MD, Oct. 21, 2016).
	18. FDA, “FDA Approves New Treatment for Inhalation Anthrax,” Press Release (Silver Spring, MD, March 21, 2016).
	19. FDA, 

	When referring to this article, please cite it as C. Challener, “FDA New Drug Approvals Down Significantly in 2016," 

Articles

As of mid-December, less than half the number of new drug approvals were issued by FDA in 2016 compared with 2015.

FDA New Drug Approvals Down Significantly in 2016

Although pharmaceutical manufacturers prefer to formulate APIs in solid-dosage form, many drug candidates do not readily form stable crystalline solids. In addition, a growing percentage of APIs in development suffer from poor bioavailability and/or other undesirable properties. There are many approaches for addressing these issues, such as the formation of amorphous dispersions, salts, and cocrystals.

	Cocrystals are attractive because, like solvates and hydrates, they allow the modification of an API’s properties without altering its chemical structure. They also provide an option for APIs that lack ionic functionality and thus cannot form salts. The synthesis of cocrystals may also be advantageous from a cost standpoint (1).

	There has been, however, significant hesitation in the pharmaceutical industry regarding the use of cocrystals since the issuance of FDA’s initial guidance on cocrystals in April 2013 (2).

	In that guidance, FDA defined cocrystals as “drug product intermediates (DPIs)” rather than APIs. This decision raised questions about expiration dates, intellectual property protections, and the consistency of the US approach with those adopted by other regulatory bodies (1).

	A new draft guidance issued by FDA in August 2016 (3) redefines cocrystals as APIs. Classified as a special case of solvates and hydrates in which the coformer is nonvolatile, cocrystals are now to have a regulatory classification similar to that of polymorphs of APIs.

	Cocrystals have crystalline lattice structures that are different from the pure API and consequently often have different physical and chemical properties. The formation of cocrystals can reduce hygroscopicity and change the particle size and shape and melting point to help overcome compaction problems for improved manufacturability. The stability of an API can also be enhanced. As importantly, dissolution properties in the body can be significantly modified. In addition, because cocrystals are neutral combinations of APIs with conformers, they can be prepared for compounds without acid or base functionality, which is required for salt formation.

	The most common property targeted for improvement via cocrystal formation is an improved aqueous dissolution rate compared to an API free acid or base, according to G. Patrick Stahly, chief operating officer at Triclinic Labs. “Cocrystals are like amorphous materials in that they provide a supersaturated concentration of an API in the body for a time sufficient for absorption to occur (a supersaturating drug delivery system),” he explains. He adds that it needs to be realized, however, that a cocrystal typically does not affect the equilibrium solubility of an API; cocrystals usually dissociate in solution because they are held together by relatively weak chemical bonds.

	Cocrystals also may offer benefits from an intellectual property perspective, according to Stahly. “At the current level of the science, it is not possible to predict cocrystal properties based on the molecular structures of the components. Solid-form screening, including cocrystal screening, is an empirical process. Since the formation of cocrystals is currently unpredictable, cocrystals that are discovered and found to have advantageous properties can be patented,” he notes.

	It should be recognized, however, that cocrystals are still not regarded as new APIs. “Drug products that are designed to contain a new cocrystal are considered analogous to a new polymorph of the API,” according to the 2016 FDA draft guidance.

	The redefinition of cocrystals as APIs is important for several reasons, according to Stahly. First, it allows the use of existing FDA guidance to provide information necessary for development. Second, existing manufacturing facilities and supply chains that make and distribute APIs can be used, and there is no need to add cocrystal manufacturing capabilities to existing drug-product manufacturing facilities. Third, API expiry dating begins at the time of cocrystal manufacture. Fourth, there is now consistency among FDA guidance, international guidance, and scientific reality.

	“After the first FDA guidance was issued, there was confusion within the pharmaceutical industry about the viability of cocrystals. My personal experiences led me to believe that scientists (myself included) were unhappy because they felt the guidance was wrong from a scientific standpoint. I believe the guidance presented unnecessary obstacles to development of cocrystals, which would discourage some companies from utilizing them. Those dealing with the facilities and regulatory issues seemed to be more pessimistic. There was talk that cocrystals were ‘dead’ in the pharmaceutical industry,” comments Stahly.

	Triclinic Labs did cocrystal screening and other development activities for clients in the period between issuance of the old and new guidance, indicating that not everyone felt that the original guidance eliminated the use of cocrystals.

	With the new guidance, however, cocrystals were, if ‘dead’ before, now ‘reborn’, according to Stahly. “The development pathway is clear and cocrystals should now be considered another tool in the box of tools used to improve solid-state properties,” he says.

	An issue addressed by the new FDA guidance is the nature of the interaction of components in a cocrystal where one component is acidic and the second component is basic. The drug manufacturer must demonstrate that there are no ionic interactions in such a cocrystal, which can be done either using the acid dissociation constants of the API and the coformer or via spectroscopic analysis.

	It is important, according to Stahly, to realize that there are various analytical techniques that can be used to probe the extent of proton transfer. “A common method is single-crystal x-ray structure determination, which is an excellent technique only if used properly. It is easy for a novice to believe protons have been actually located when often they are simply left to ride on the atom to which they are bonded; the protons are in assumed instead of refined positions,” he notes. A single-crystal study is not always necessary, however, and other techniques such as infrared (IR) spectroscopy can often be used.

	What drove the agency to make this significant change to its guidance on cocrystals? Stahly believes the strong response from industry was the major driving force. In 2012 at an Indo-US Bilateral Meeting held from Feb. 2-4, 2012, 46 attendees co-authored a publication presenting their consensus “… on the need to define cocrystals more broadly and to classify them like salts” and their recommendation “… that the classification of cocrystals in pharmaceutical science should be consistent with current scientific thought” (4).

	Also in 2012, a working group of the International Consortium for Innovation & Quality in Pharmaceutical Development (IQ Consortium) submitted a comment paper to FDA recommending that “FDA considers classification of co-crystals within existing guidance[s], which provides discrete, industry understood points where quality attributes are measured and controlled to ensure product quality and patient safety (i.e., the drug substance and drug product)” (5).

	“The primary messages from those groups were that the original guidance was inconsistent with both current scientific understanding of the nature of cocrystals and existing FDA guidance relating to drug development. In addition, the guidance would lead to negative regulatory and manufacturing consequences and be inconsistent with the European Medicines Agency provisional guidance outlining submission requirements for cocrystals. It appears that FDA seriously considered industry’s comments and revised the guidance,” Stahly observes.

Guidance for Industry: Regulatory Classification of Pharmaceutical Co-crystals

 (Silver Spring, MD, April 2013).
	3. FDA, 

Draft Guidance for Industry: Regulatory Classification of Pharmaceutical Co-crystals

 (Silver Spring, MD, Aug. 2016).
	4. S. Aitipamula, et al., 

.12, 2147-2152 (2012).
	5. IQ Consortium, “IQ Comments on FDA Draft Guidance Regulatory Classification of Pharmaceutical Co-Crystals,” March 1, 2012.

Previous hesitation by pharma industry to use cocrystals may change with FDA’s new guidance that classifies cocrystals APIs.

New Opportunities for Cocrystals

Cross-coupling reactions enable the synthesis of complex building blocks and intermediates with structural motifs common in many classes of APIs. Numerous cross-coupling methodologies that allow the reaction of unsaturated substrates (acetylenes, alkenes, aryls) with a wide range of functionalized organohalides have thus been employed in the commercial manufacture of APIs. These reactions, however, are typically mediated by expensive and often toxic palladium catalysts with specially designed ligands. Consequently, there is significant interest in developing alternative catalyst systems that avoid these issues.

	Advances in cross-coupling chemistry have had a significant impact on API synthesis at commercial scale, according to Chris Senanayake, vice-president of chemical development in the United States at Boehringer Ingelheim Pharmaceuticals. “The expanded substrate scope, the availability of a variety of novel ligands, and the in-depth mechanistic understanding of cross-coupling reactions have led to shorter development times and enhanced process robustness,” he notes.

	The most commonly used cross-coupling reactions, most of which are catalyzed by palladium-based, transition-metal complexes, include Suzuki and Sonogashira coupling, according to Jeff Song, director of development, also with Boehringer Ingelheim Pharmaceuticals.

	When first developed, the Suzuki reaction involved the cross coupling of aryl organoboronic acids with halides. Today, the substrate scope is much broader and includes alkyl, alkenyl, and alkynyl compounds. In addition, potassium trifluoroborates and organoboranes/boronate esters can be used instead of boronic acids, while in some cases triflates or other pseudohalides can be used instead of actual organohalides.

	The Sonogashira reaction involves the coupling of terminal alkynes with aryl or vinyl halides. In addition to the palladium catalyst, a copper(I) cocatalyst and an amine base are required. When first introduced, maintaining anhydrous and oxygen-free conditions was essential for this coupling method, but newer versions do not require such strict control of the reaction environment.

	Suzuki reactions at Boehringer Ingelheim
	In the past few years, scientists at Boehringer Ingelheim have employed Suzuki coupling chemistry for the preparation of FLAP (1), HCV Polymerase (2), and 11-β-HSD 1 inhibitors (3). In the first case, a Suzuki reaction was used to form the key biaryl bond between an aryl bromide and aminopyrimidine boronic acid. In the second example, a one-pot sequential borylation−Suzuki coupling process was devised to efficiently couple 2-iodo-5-bromopyrimidine and a 2-bromoindole substrate. The third reaction involved a Suzuki coupling using a pyridone boronic acid on scale.

	“Non-precious-metal catalysis is a new horizon for the field of cross coupling,” observes Senanayake. “Iron, copper, cobalt, and nickel catalysts for cross-coupling reactions have begun to be applied on large scales,” he adds.

	In fact, Boehringer Ingelheim, Pfizer, and AbbVie have formed a cross-company consortium with the aim of jointly driving research in this area. The goal of the Non-Precious-Metal Catalysis Alliance is to advance the development of abundant-metal catalysts and replace precious-metal catalysts in the synthesis of APIs.

	“The use of non-precious-metal catalysis on large scales will greatly improve the economics and sustainability of chemical processes,” asserts Song. He points to a recent example from Boehringer Ingelheim that involves an iron-catalyzed Kumada coupling reaction under flow conditions (4). In the reaction, 2-chloropyrazine can be coupled with various aryl Grignard reagents with catalyst loadings as low as 0.5 mole percent. Switching from batch to continuous processing avoided large exotherms, providing a longer catalyst lifetime and higher yields. The scale-dependent issues often observed with Kumada coupling reactions were also eliminated, making scale up easier.

	A key area for additional development in coupling chemistry, according to Song, is their use in the synthesis of chiral compounds. “In the next few years, we expect to see further advancement in methodology development for asymmetric cross couplings, including for biaryl and sp

 coupling reactions. In fact, significant progress has recently been made, as exemplified by the asymmetric Suzuki reactions using ligands developed at Boehringer Ingelheim,” he notes.

	For instance, novel monophosphorous ligands that are chiral at the phosphorus atom were employed for the palladium-catalyzed asymmetric Suzuki-Miyaura coupling of aryl boronic acids with aryl halides in the presence of tripotassium phosphate to afford functionalized chiral biaryls compounds under mild conditions and up to 96% enantiomeric excess (5). These reactions were applied to the asymmetric synthesis of an atropisomeric HIV integrase inhibitor on large scales (6). Similar asymmetric coupling reactions were used to achieve the first total syntheses of biaryl natural products korupensamine A and B (7).

	Silicon-based cross-coupling reactions have recently been shown to have potential advantages over existing cross-coupling chemistry, particularly with respect to alkyl-aryl and alkyl-alkenyl (sp

) cross-couplings, according to Gerald L. Larson, a senior research fellow at Gelest.

	Because the energy barrier for these couplings is high, reactions with transition-metal catalysts must be run under extreme conditions or using highly reactive substrates, which prevents the incorporation of many functional groups.

	The newer silicon-based reactions involve both photoredox and cross-coupling catalysts to facilitate cross-coupling reactions of a variety of substrates, such as trifluoroborates and carboxylic acids. Unlike traditional cross-coupling reactions mediated by palladium, these dual-catalyst reactions proceed via radical mechanisms. As a result, they are not plagued by the high-energy barriers that exist for conventional cross-coupling reactions.

	Gary A. Molander and his research group at the University of Pennsylvania have been very active in this area (8). Organosilicates such as alkylbis(catecholato)silicates serve as excellent radical precursors for nickel/photoredox dual catalysis. The organosilicates undergo single-electron oxidative fragmentation upon exposure to visible light in the presence of a ruthenium catalyst. The generated radicals then participate in single-electron transmetallation mediated by more environmentally friendly and less expensive nickel complexes.

	One benefit of this approach, according to Larson, is the greater stability of the nucleophilic partners used in the cross-coupling reactions. In addition, the organosilicates are easily prepared from readily available precursors. “The ability to cross couple alkyl and, particularly primary alkyl groups in sp

 cross-coupling protocols, as well as the ability to cross couple nucleophilic substrates containing unprotected amino groups are key advantages,” he adds. The use of nickel rather than palladium also reduces the overall cost and eliminates the need to remove the metal from the final reaction mixture, according to Larson. “As importantly,” he observes, “there is no need to synthesize boronic acids, silanols, trifluoroborates, or zinc reagents, and both preparation of the silicate reagents and the cross-coupling reactions are fully scalable.”

. 80 (3) 1651-1660 (2015).
	2. Y. Zhang et al. 

. 16 (17) 4558-4561 (2014).
	3. Y. Zhang et al. 

. 81 (6) 2665-2669 (2016).
	4. F. G. Buono et al., 

. 2016 (15) 2599-2602 (2016).
	5. W. Tang et al., 

. 14 (9) 2258 (2010).
	6. K. R. Fandrick et al., 

. 54 (24) 7144 (2015).
	7. G. Xu et al., 

. 136 (2) 570-573 (2014).
	8. J.C. Tellis et al., 

	When referring to this article, please cite it as C. Challener, “New Horizons for Cross-Coupling Reactions," 

Non-precious-metal catalysts are increasingly employed for commercial API synthesis.

New Horizons for Cross-Coupling Reactions

Effective microbiological testing during biopharmaceutical drug development and manufacturing is crucial for ensuring sterility, determining antimicrobial effectiveness, detecting microbial contamination or bioburden levels, analyzing endotoxins, and implementing environmental monitoring programs.

	Growing pressures to increase productivity, flexibility, and cost-effectiveness and the unique properties of many next-generation therapies are challenging today’s microbiologists.

Pressures to accelerate current and next-gen therapies are challenging traditional microbiological testing models.

Microbiological Testing: Time is of the Essence

A small-molecule APIs become increasingly complex, designing concise, practical, and economical synthetic routes for their commercial production becomes increasingly challenging. There is, consequently, growing demand for cost-effective, highly efficient catalysts that mediate atom-economical, environmentally friendly transformations that can replace traditional, non-catalytic processes that require multiple steps. A summary of selected new catalysts that show promise for pharmaceutical intermediate and API synthesis is presented in the following.

	Silicon-containing compounds are of interest as potential drug candidates because silicon can impart greater stability and lead to compounds with improved solubilities and pharmacokinetic properties. There are two common routes to heteroarylsilanes: stoichiometric reaction of a silicon electrophile with a heteroaromatic organometallic intermediate (prepared via a Grignard reaction) or rhodium- or iridium-catalyzed C-H silylation in the presence of an excess of a hydrogen acceptor. Neither approach is practical on an industrial scale, and both suffer from limited functional group tolerance.

	Researchers in the Grubbs and Stoltz groups at the California Institute of Technology fortuitously discovered an attractive alternative method based on the inexpensive base potassium tert-butoxide (KOtBu) (1). When investigating a reaction to convert biomass to chemicals via the breakage of C-O bonds using an iron catalyst, KOtBu, and a hydrosilane as a hydride equivalent, they observed that silylated heteroaromatics were formed in minor quantities in a control reaction using only KOtBu and the hydrosilane. In addition, they noted that the yield of silylated products increased as the reaction temperature decreased.

	The cross-dehydrogenative heteroaromatic C-H silylation reaction with hydrosilanes was found to proceed best using a catalytic amount of KOtBu (1-20 mol%) in the absence of an acceptor, with only hydrogen gas as the byproduct. The fact that a common base catalyzes this important reaction was quite surprising, and thus the researchers went to great lengths to confirm that the KOtBu was indeed the catalyst and not some unknown impurity.

	The reaction is believed to proceed via a radical mechanism that is completely different from the mechanisms observed with transition-metal catalysts. Its scope is also very broad. Indoles with a variety of substituents on the nitrogen and various positions on the arene ring and many different electron-neutral and electron-rich N-, O-, and S-containing heterocyclic compounds are suitable substrates. Carbonyl groups are generally not tolerated except when protected as acetals. Some groups (bromide, iodide, cyano, and nitro substituents) do hinder the reaction. Interestingly, fluoride, chloride, trifluoromethyl, epoxide, N-alkyl aziridine, pyridine, and tertiary amine and phosphine groups do not.

	Notably, even simple arenes serve as good substrates. Substitution affects the regioselectivity; however, ortho-substitution occurs with anisole, while directing-group-free C(sp3)-H silylation leads to silylated benzyl derivatives with toluene and similar compounds. The researchers are also exploring the reaction of non-aromatic compounds (e.g., aliphatic compounds, alkenes, and alkynes).

	The scientists have also shown that the cross-dehydrogenative heteroaromatic C-H silylation reaction is scalable. When run neat using N-methyl indole and 1.5 equivalents of triethylsilane at 45 °C on a 100-gm scale, desired C2 silylated product was obtained in 76% yield with a greater than 20:1 regioselectivity after simple filtration and distillation.

	The researchers also demonstrated the utility of the reaction by silylating the antihistamine thenalidine and the antiplatelet drug ticlopidine in 58-68% yield with high chemo- and regioselectivity, indicating the applicability of the transformation for late-stage modification of pharmaceutically relevant compounds.

	Sites of unsaturation (alkenes in particular) are widely present in pharmaceutical compounds and their introduction can be achieved using a variety of methods, such as the elimination of alcohols, halides or other leaving groups, the reduction of acetylenes, and Wittig and Diels-Alder reactions. Dehydrogenation of alkanes is highly attractive because it allows for the flexible placement of alkenes. In addition, when performed under acceptor-less or terminal oxidant-free conditions, only hydrogen is generated as the byproduct. It is, however, a highly endothermic reaction traditionally mediated by expensive noble-metal catalysts at high temperature. Enzyme-based systems do proceed at room temperature, but require the use of a full equivalent of a terminal oxidant, and thus hydrogen recovery is not possible.

	Scientists at Princeton University have overcome these issues with the development of a reaction that is noble-metal-free, does not require the use of a terminal oxidant (and thus generates hydrogen), and proceeds at mild temperatures (2). Their approach is based on key aspects of the iron-based desaturase system, which catalyzes dehydrogenation reactions via step-wise hydrogen atom removal. The first hydrogen atom transfer (HAT) occurs from the alkane substrate to a high-valent oxo species, which is much more difficult than the second, which can occur via HAT or electron transfer followed by proton transfer.

	In their new approach, the researchers use cooperative catalysis with a dual-catalyst system to achieve the two steps. The polyoxometalate tetra-n-butylammonium decatungstate (TBADT) is easy to synthesize and has been shown to mediate HAT reactions of unactivated alkanes under near-UV light irradiation. For the second catalyst, the researchers were interested in cobaloximes because they are known to catalyze radical reactions including the reversible formation of alkenes and cobalt hydrides and have been shown to mediate water reduction under photo-irradiation conditions. Cobaloxime pyridine chloride (COPC) was selected because it is also readily synthesized.

	When used together (1.5 mol% TBADT and 0.75 mol% COPC) under irradiation at 323 nm, which is the absorbance maximum of TBADT, cyclooctane was converted to cyclooctene in 23% yield. The researchers also showed that cyclopentane was converted to cyclopentene and cyclopentadiene, while cyclohexane was dehydrogenated to cyclohexane rather than benzene, which commonly occurs under noble-metal catalysis.

	The reactivity of ethyl isovalerate was also interesting. Rather than produce the thermodynamically most stable product, which is generally the case with noble-metal catalysts, the dehydrogenation proceeded to form the skipped-enone product. The researchers are also exploring the tolerance for functional groups other than esters.

	While the initial results of the cooperative catalysis approach with simple alkanes are not as efficient as reactions with noble-metal catalysts, the researchers believe there is potential to improve the reaction. In fact, when secondary alcohols are used as substrates, the yields increase (i.e., 83% for 1-phenylethanol).

	Researchers at the Scripps Research Institute (TSRI) developed a catalyst that mediates C-H activation in the synthesis of heterocycles (3). Using an N-methoxy amide group as both a directing group and an anionic ligand, the PdX2 (X = ArCONOMe) catalyst is generated in situ from a Pd(0) source using air as the oxidant. With the PdX2 species localized near the target C-H bond, the natural preference of the metal to coordinate to the heteroatom is avoided. The catalyst has been used to synthesize a number of different compound types, including furans, benzofurans, benzothiophenes, indoles, pyrroles, thiazoles, pyrazoles, imidazoles, pyridines, quinolines, pyrazines, pyrimidines, pyrazoles, and thiazoles.

	Catalysts that mediate other types of C-H activation reactions have also been developed by TSRI researchers. In one case, sequential diarylation is achieved to afford non-natural β -Ar-β-Ar’-β-α-amino acids with diastereomeric ratios of greater than 20:1 (4). These compounds are building blocks for peptide drugs with structural diversity that may make them resistant to enzyme degradation. In the second reaction, palladium-catalyzed enantioselective C-H iodination is used to achieve the kinetic resolution of chiral amines (5). Notably, the reaction proceeds at room temperature and involves only inexpensive and commercially available reagents.

	Coupling of heteroatom-substituted olefins

	Carbon-carbon coupling reactions have become, in recent years, fundamental transformations for the commercial production of small-molecule APIs. Researchers at TSRI recently developed a new coupling reaction for the preparation of highly substituted, uniquely functionalized compounds catalyzed by an inexpensive iron complex (6). The reaction is also attractive because it is performed open to the air at room temperature.

	While typically run in ethanol, the researchers showed that reactions run in vodka, gin, whiskey, tequila, beer, and wine also afforded the desired coupling products. In addition, they demonstrated the broad scope of the reaction by synthesizing more than 60 different compounds, most of which were new chemical entities not previously reported.

, 518, 80-84 (2015).
	2. J. G. West, D. Huang, and E.J. Sorensen, 

, 515, 389-393 (2014).
	4. J-Q Yu, et al., 

, 343 (6176), 1216-1220 (2014).
	5. J-Q. Yu, et al., 

, 346 (6208), 451-455 (2014).
	6. P.S. Baran, et al., 

New catalysts show promise for pharmaceutical intermediate and API synthesis.

Cost-Effective Catalysts Could Replace Traditional Multi-Step Processes

	When referring to this article, please cite it as C. Challener, “’Rebirth’ of Cocrystals?" 

FDA redefines cocrystals as APIs and not drug-product intermediates.