Improving API Synthesis - Pharmaceutical Technology

Latest Issue

Latest Issue
PharmTech Europe

Improving API Synthesis
O-arylation and O-alkylation, a one-pot protein synthesis, a combined approach in continued and chemocatalysis, and green-chemistry applications are the target of some recent advances in API synthesis.

Pharmaceutical Technology
Volume 35, Issue 8, pp. 52-56

Green-chemistry applications

Green chemistry is an important tool in improving reactions, which may for example, improve production economics through reduced energy requirements, lower solvent use, fewer byproducts, and less waste generation. Bruce H. Lipshutz, professor in the chemistry and biochemistry department at the University of California at Santa Barbara, was recognized in June with a Presidential Green Chemistry Challenge Award, an annual recognition by the US Environmental Protection Agency for advances in green chemistry (11).

Nanodispersed surfactant . Lipshutz was recognized for designing a second-generation surfactant, TPGS-750-M, which can be used in industrial processes to replace large amounts of organic solvents with small amounts of the surfactant nanodispersed in water only. TPGS-750-M is composed of tocopherol (i.e., vitamin E), succinic acid, and methoxy polyethylene glycol. TPGS-750-M forms nanomicelles in water that are lipophilic on the interior and hydrophilic on the exterior. A small amount of TPGS-750-M may be used to spontaneously form 50–100-nm diameter micelles in water to serve as nanoreactors. The particle size of TPGS-750-M is engineered to facilitate organic reactions, such as cross-couplings. Reactants and catalysts dissolve in the micelles, resulting in high concentrations that lead to increased reaction rates at ambient temperature (11).

Several common organic reactions that are catalyzed by transition metals can take place within TPGS-750-M micelles in water at room temperature and in high isolated yields. These reactions include ruthenium-catalyzed olefin metatheses (Grubbs), palladium-catalyzed cross-couplings (Suzuki, Heck, and Sonogashira), unsymmetrical aminations, allylic aminations and silylations, and aryl borylations. The technology also offers the potential for palladium-catalyzed aromatic carbon–hydrogen bond activation for carbon–carbon bond formation at room temperature. In its awards recognition, EPA cited other advantages to the technology: straightforward product isolation; elimination of frothing and foaming commonly associated with other surfactants; efficient recycling of the surfactant after use; recovery of the insoluble product by extraction; and reuse of the aqueous surfactant with negligible loss of activity. Future generations of surfactants may include a catalyst tethered to a surfactant to provide both the reaction vessel (i.e., the inside of the micelle) and the catalyst to enable the reaction (11).

Flow processing . Eli Lilly submitted two entries to EPA's Green Chemistry Presidential Challenge. The first involved the commercial production of LY2624803*H3PO4, an investigational new drug candidate in Phase II clinical trials and a drug acquired by Lilly with its acquisition of Hypnion. The original synthesis was not amenable to large-scale manufacture and had several environmental and safety issues with the original chemistry. Among them were: dimethylformamide/sodium hydride in step one of the synthesis; methylene in various steps; a molten step with observed self-heating; an aldehyde purification that would be unsafe at increased scale; phosphoryl chloride in large excess; and chromatographic purification (11).

The company made several improvements to the synthesis using flow processing. An efficient carbonylation replaced an inefficient oxidation catalyzed by tetramethyl pentahydropyridine oxide. Hydrogen replaced sodium triacetoxyborohydride in a reductive amination. Although both operations required high pressure (i.e., 1000 psi), which would be difficult to manage in a batch environment, both operations were amenable to flow processing (11).

Process mass intensity (PMI), a measure of the efficiency of a synthesis, was improved. PMI is the total mass of raw materials (including water) put into a process for every kilogram of product produced. The original route had a PMI of more than 1000 before chromatography. The new route has a net PMI of 59, representing a 94% reduction in PMI and a 96% percent reduction with chromatography. Lilly implemented its new route for LY2624803*H3PO4 on a pilot-plant scale in Indianapolis, Indiana, during 2009 and on a commercial scale in Kinsale, Ireland, during 2010, according to the EPA report (11).

Improved Grignard chemistry. Another entry from Eli Lilly involved the development of Grignard chemistry using a continuous stirred tank reactor. The Grignard reaction is applied to many industrial reactions, including producing intermediates for pharmaceutical compounds. Some commercial-scale problems with the reaction, however, are strongly exothermic activation and reaction steps, heterogeneous reactions with potential problems suspending and mixing the reaction mixture, and operational hazards posed by ethereal solvents, such as diethyl ether (11).

Eli Lilly developed inherently safer Grignard chemistry using a continuous stirred tank reactor that allowed continuous formation of Grignard reagents with continuous coupling and quenching. This approach minimized hazards by operating at a small reaction volume, performed metal activation only once during each campaign, and used 2-methyltetrahydrofuran (MeTHF). MeTHF offers certain advantages, such as that it may be derived from renewable resources and may provide improved chemoselectivity and stereoselectivity compared with Grignard products using other ethereal solvents. The continuous approach provided reductions of 43% in metal use, 10% in Grignard reagent stoichiometry, and 30% in PMI (11) According to the EPA report, Lilly is using the continuous stirred tank reactor Grignard approach to produce two key materials: the penultimate intermediate of LY2216684*HCl, a norepinephrine reuptake inhibitor currently under clinical investigation, and for an intermediate for another drug under clinical development. Commercial production on a 22-L scale is under consideration (11).

Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072,


blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
| Weekly

What role should the US government play in the current Ebola outbreak?
Finance development of drugs to treat/prevent disease.
Oversee medical treatment of patients in the US.
Provide treatment for patients globally.
All of the above.
No government involvement in patient treatment or drug development.
Finance development of drugs to treat/prevent disease.
Oversee medical treatment of patients in the US.
Provide treatment for patients globally.
All of the above.
No government involvement in patient treatment or drug development.
Jim Miller Outsourcing Outlook Jim MillerOutside Looking In
Cynthia Challener, PhD Ingredients Insider Cynthia ChallenerAdvances in Large-Scale Heterocyclic Synthesis
Jill Wechsler Regulatory Watch Jill Wechsler New Era for Generic Drugs
Sean Milmo European Regulatory WatchSean MilmoTackling Drug Shortages
New Congress to Tackle Health Reform, Biomedical Innovation, Tax Policy
Combination Products Challenge Biopharma Manufacturers
Seven Steps to Solving Tabletting and Tooling ProblemsStep 1: Clean
Legislators Urge Added Incentives for Ebola Drug Development
FDA Reorganization to Promote Drug Quality
Source: Pharmaceutical Technology,
Click here