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Syntex/Roche Highlights

A Safe and Efficient Manufacturing Process for Oseltamivir Phosphate (Tamiflu®). Tamiflu® blocks formation of the neuraminidase protein, one of the two major surface structures of influenza virus. Tamiflu® is the only antiviral for the treatment and prevention of influenza A and B. Avian flu pandemic planning has spurred strong sales growth, with sales exceeding $1 B for the first time in 2006.  We developed a safe and efficient non-azide process, utilizing diallylamine and tert-butylamine as ammonia surrogates and palladium catalysis, which can be implemented in a multi-purpose manufacturing facility to meet pandemic supply demands.

A Safe and Efficient Process for a Pyrazolo[3,4-b][1.4]benzodiazepine Mitosis and Angiogenesis Inhibitor. The induction of growth of blood vessels from surrounding tissue into a solid tumor is termed tumor angiogenesis. The new blood vessels supply nutrients and oxygen which are important for tumor growth, invasion, and metastasis. Angiogenesis inhibitors can “normalize” abnormal tumor vasculature. This “normalization” may inhibit shedding of cancer cells into the circulation (leading to metastasis) and improve the delivery of chemotherapeutic agents. Thus, a synergistic anticancer effect might be expected when low dose angiogenesis inhibitors are used in combination with other chemotherapeutic inhibitors. We developed a new synthetic sequence to Roche’s promising pyrazolo[3,4-b][1.4]benzodiazepine mitosis and angiogenesis inhibitor (MAI). Process modifications were made with a focus on addressing scale up concerns, increasing overall efficiency, and minimizing solids handling of the highly potent product. This process provided material for clinical trials.

A New Method for Ring Construction of the Highly Functionalized Pyridine Core of NK-1 Receptor Antagonists. NK-1 Receptors are widely distributed in the central nervous system (CNS) and peripheral tissue. Clinical trials have highlighted the therapeutic potential of NK-1 receptor antagonists for treatment of depression and anxiety and control of chemotherapy-induced nausea and vomiting. We constructed Roche’s “inverse nicotinamides”, befetupitant and netupitant, from commodity components using a new and general pyridine ring construction method suitable for long-term supply on a metric ton scale.

A Green Process for Carvedilol. Carvedilol (Coreg®) is a highly effective drug for the treatment of high blood pressure, mild to severe chronic heart failure, and left ventricular dysfunction. Coreg® is marketed by GSK in the US and Canada ($1.4 B sales in 2006) and by Roche in Europe. The first generic carvedilol was approved by the FDA in September 2007. The key intermediate, 4-hydroxycarbazole, is currently produced by an inefficient (50%) Fisher Indole synthesis using polyphosphoric acid. We reduced the cost-of-goods and eliminated the phosphate waste using a novel palladium(II) catalyzed oxidation where the palladium(II) oxidant is continuously regenerated by the conversion of 4-bromotoluene to toluene.

An Optimal Manufacturing Process for Actelion’s Bosentan. Bosentan, an oral ETA/ETB receptor antagonist, improves exercise capacity, quality of life, haemodynamics and time to clinical worsening of patients with pulmonary arterial hypertension (PAH). Marketed as Tracleer® by Actelion Pharmaceuticals, annual sales were up 42% to CHF 899 M in 2006. We developed a manufacturing process from the first generation process. A cascade of process improvements resulted in an overall yield increase from 67% to 84% and an API purity increase from 99.3% to 99.7%.

The First Efficient Asymmetric Route to Orlistat.  The weight-loss drug Orlistat blocks the absorption of some fat in the intestines. Orlistat has been marketed by Roche as the prescription drug Xenical® since 1999 and by GlaxoSmithKline as the over-the-counter drug Alli® since 2007. Xenical® US sales have been disappointing, peaking at $202 M in 2000 and dropping to $86.5 M in 2005. Alli® annual sales are projected to be $100-200 M. We demonstrated that an asymmetric manufacturing process is a viable alternative to the late-stage resolution of the current manufacturing process.

Method for Manufacture of S-Phenylcysteine, a Key Component of Nelfinavir Mesylate. Nelfinavir mesylate is marketed as Viracept® by Roche in Europe and by Pfizer in the US, Canada, and Japan. Nelfinavir mesylate is a potent, orally bioavailable inhibitor of HIV-1 Protease. It is a key component of many antiretroviral drug cocktails. Roche Viracept® sales were $160 M in 2006. We developed two new strategies for preparing S-phenylcysteine which avoided the racemization, low yield, and undesirable reagents (triphenylphosphine, diethylazodicarboxylate, thiophenol, sodium hydride) of the first generation route.

A One-Pot Manufacturing Process for Acyclovir. Acyclovir is one of the top three antiviral drugs for the treatment of genital herpes, an incurable infection caused by the herpes simplex virus (HSV). The global annual sales for these antiviral drugs was $1.4 B in 2004. Our acyclovir process is unique in reacting 1,3-dioxolane with an unprotected guanine, is selective for the desired N9 alkylation, and can be run from start to finish in a single pot.

Two Manufacturing Processes for Ketorolac: A Pyrrole-2-Acetate via Pyrrole Ring Construction from a 1,3-Diene and via Selective Monoalkylation of Pyrrolemagnesium Chloride. Ketorolac, marketed under the Roche brand name Toradol®, is now also available as a generic. Primarily used for post-operative pain, ketorolac is the only non-opioid injectable analgesic approved for sale in the US. Sales in the US in 2006 were 43 million units, about 9% of the injectable analgesic market. Anticipating the transition to generic ketorolac, we identified and developed two new routes to pyrrole-2-acetates and the pyrrolopyrrole core. In the first route, we demonstrated a novel method for converting a 1,3-diene to a pyrrole, including the conversion of 3,5-hexadienoic acid to pyrrole-2-acetic acid. In the second route, we prepared the pyrrole-2-acetic acid by monoalkylation of pyrrole via pyrrolemagnesium halide. To achieve the necessary high selectivity for pyrrole monoalkylation, we cultivated a supplier for the, at the time, unknown Grignard reagent methylmagnesium chloride in butyl diglyme.      

A Green Alternative to Ammonia for Synthesis of the Heterocyclic Core of Ticlopidine and Plavix®. Ticlopidine, marketed by Roche as Ticlid®, is approved for the prevention of recurrent stroke in patients who have already had a stroke or TIA and who are unable to take aspirin. Ticlid® sales were $200 M in 1998. Sanofi-Aventis and Bristol-Myers Squibb (BMS) market Plavix®, the anti-stroke blood thinner with the same heterocyclic core. Plavix® sales were $5.9 B for 2005, an increase of 16% over 2004. We demonstrated for Sanofi-Aventis an efficient one-pot Green approach for converting thiophene, via 2-(2-thienyl)ethanol, to 2-(2-thienyl)ethylamine.

Organotransition Metal Methods for the Manufacture of Naproxen. The anti-arthritic drug Naproxen, marketed by Syntex as Naprosyn® and Anaprox®, was the fifth best-selling drug in the world and third-best selling drug in the US in 1988. Naproxen accounted for over 50% of Syntex $1.4 B in sales that year. Anticipating the patent expiration, Syntex and P&G obtained FDA approval in 1994 for an OTC version, marketed as Aleve®. We evaluated and developed several transition metal-based strategies for introducing the chiral propionate side chain. See: “Twenty Years of Naproxen Technology”, Org. Proc. Res. Dev. 1997, 1, 72.


The First Total Syntheses of Ergot Alkaloids Clavicipitic Acid and Aurantioclavine:  Highlighting the Synthetic Utility of Palladium Catalyzed Transformations. We constructed and functionalized indoles using four palladium catalyzed processes (Hegedus Olefin Amination, Heck Olefination of an aryl iodide in the presence of an aryl bromide,  Heck Olefination of an aryl bromide, and a novel palladium(II) catalyzed displacement of an allylic oxygen).


Medicinal and Process Chemistry Leading to Eli Lilly’s Pemetrexed. We reported the first synthesis of 5,10-dideazatetrahydrofolic acid (DDA-THF). DDA-THF blocked purine biosynthesis and showed unusually powerful anticancer activity against a wide range of solid tumors. These promising results led to a collaboration between the Taylor group at Princeton and Eli Lilly & Co. The collaboration produced the 5-membered ring analog pemetrexed, now marketed by Lilly as Alimta®, a chemotherapy drug for patients with malignant pleural mesothelioma. Royalties from the Princeton-Lilly licensing agreement provided funds for a new chemistry building at Princeton University.