Single-Enantiomer Drugs Drive Advances in Asymmetric Synthesis

The prevalence of chiral medicinal compounds in the current pharmaceutical market and in the industry's pipeline is a driving force for fine chemical companies to enhance their toolboxes. They are responding by advancing chemocatalysis and biocatalysis as a means to cost effectively produce chiral intermediates and to direct stereoselectivity in asymmetric reactions.

"What is interesting to see is how single enantiomer drugs have now become the standard when working with chiral compounds in the pharmaceutical industry," says Sandra Erb, manager of Technology Catalysts International's (Falls Church, VA, www.technology-catalysts.com) chirals and fine chemicals practice. "Barring a specific problem that may limit a racemate from being developed through an asymmetric route, pharma companies will develop the single enantiomer. It is really a case of the chemical development side of pharmaceutical manufacturing advancing to such a point that it has now become a base requirement for fine chemical companies to have capabilities in asymmetric synthesis as part of their toolbox."

Form of active ingredient among the top 10 selling prescription drugs, US, 2005

Single enantiomers dominate theTop-selling US prescription drugs

The importance of chiral technologies is underscored by the prevalence of single enantiomer drugs among the top-selling drugs. Among the top 10 selling US prescription pharmaceuticals in 2005, seven are small molecules, and six of these are single enantiomers, says Erb. This list includes the two top-selling drugs: "Lipitor" (atorvastatin) by Pfizer Inc. (New York, NY, www.pfizer.com) and Merck & Co. Inc.'s (Whitehouse Station, NJ, www.merck.com) "Zocor" (simvastatin).

AstraZeneca PLC's (London, England, www.astrazeneca.com) "Nexium" (esomeprazole), ranked third in US prescription drug sales, is a racemic switch of AstraZeneca's former blockbuster gastrointestinal drug "Prilosec" (omeprazole). Esomeprazole is the S-entantiomer of omeprazole. "It is one of the most successful racemic switches launched," says Erb. A racemic switch refers to the conversion of a racemic mixture into its isolated enantiomers. "With this racemic switch and the launch of Nexium, AstraZeneca was able to position itself against generics competition with the patent expiration of Prilosec," says Erb.

GlaxoSmithKline PLC's "Advair Diskus" (fluticasone and salmeterol) contains a single enantiomer (fluticasone) and a racemate (salmeterol). "Plavix" (clopidogrel) is a single enantiomer developed by Bristol-Myers Squibb Company (Princeton, NJ, www.bms.com) and Sanofi-Aventis (Paris, France, en.sanofi-aventis.com).

Rounding out the list of single enantiomer small molecules is Pfizer's "Zoloft" (sertraline). Zoloft was one of the first antidepressants among the selective serotonin re-uptake inhibitors to be developed as a single enantiomer, explains Erb.

Tap Pharmaceutical Products Inc.'s (Lake Forest, IL, www.tap.com) "Prevacid" (lansoprazole) is the only drug among the top 10 selling US prescription drugs (small molecules) still marketed as a racemate, notes Erb. The three remaining drugs in the top ten are biologics: Amgen Inc.'s (Thousand Oaks, CA, www.amgen.com) "Epogen" (epoetin alfa), Johnson & Johnson Company's (New Brunswick, NJ, www.jnj.com) "Procrit" (epoetin alfa), and Amgen's "Aranesp" (darbepoetin alfa).

"What this shows is that chemical development has caught up to the demand by pharma companies to develop single enantiomers when working with medicinal compounds that are chiral," says Erb. Although the push for single enantiomer drugs first intensified in the 1990s, it continues to be an important area of investment for fine chemical companies.

"This was evident at Informex this year, with many companies promoting their capabilities in chiral chemistry," says Erb. "It has become a requirement for doing business in fine chemicals."

BASF advances chiral intermediates

BASF AG (Ludwigshafen, Germany, www.basf.com), the number one global chemical company, is a case in point with several new developments in chiral chemistry. These include a new biocatalytic route for producing chiral alcohols and chiral epoxides; the introduction of two new chiral amines; the launch of a new biocatalysis unit in its chiral intermediates business; and an increase in specialty amine capacity.

BASF launched in February a new production technology to manufacture chiral alcohols and chiral epoxides using an epoxide hydrolase. The new technology adds to its toolbox in producing chiral alcohols and chiral epoxides that use other biocatalytic routes based on lipases and dehydrogenases and chemoselective routes using asymmetric hydrogenation and Corey-Bakshi-Shibata reduction.

The new technology uses a hydrolase for selective epoxide ring-opening to produce various chiral intermediates. "We see the hydrolase technology as an improvement over existing technology to make chiral intermediates," says John Banger, manager, new business development, chemicals with BASF's intermediates group. "By using a biocatalytic route, we do not have metals in the process, and it is applicable to multiple nucleophiles."

Sharpless asymmetric epoxidation and Jacobsen hydrolytic kinetic resolution are two well-established routes for making chiral epoxides and diols. These process routes are respectively based on the work of K. Barry Sharpless, professor of chemistry at the Scripps Research Institute (San Diego, CA, www.scripps.edu) and the recipient of the 2002 Nobel Prize in Chemistry, and Eric Jacobsen, professor of chemistry at Harvard University (Cambridge, MA, www.harvard.edu).

These chemocatalytic routes, however, both use heavy-metal-based chemical catalysts to separate the racemic epoxides to produce the single enantiomer epoxides and diols, explains Banger. "The advantage of using a biocatalytic route for separating the racemic epoxides is that there is no heavy metal in the process, and it can also be used with a wide variety of nucelophiles, leading to a number of different chiral product families."

BASF also recently added two new chiral amines to its toolbox: (R, R)- and (S, S)-bis (1-phenylethyl) amine, which can be used for the asymmetric synthesis of nonnatural amino acids and as starting materials for chiral bases (i.e., bases for deprotonation according to Simpkins' reactions).

BASF has 1000 tons of annual commercial-scale capacity (under current good manufacture practices) for chiral amines at its main manufacturing site in Ludwigshafen, Germany. The commercial-scale capabilities complement its R&D and pilot-scale capabilities at Ludwigshafen. The chiral amines produced at Ludwigshafen are for pharmaceutical manufacture and are part of its overall production network in specialty amines.

BASF operates a large-scale amines plant in Geismar, Louisiana for producing S-methoxyisopropylamine, a chiral intermediate produced captively in manufacturing a BASF herbicide. In March, BASF announced it was building a new alkylethanolamine plant in Geismar that increases its global capacity by roughly 40 percent. Although the capacity is primarily targeted for industrial applications such as in water treatment, coatings, and polyurethane catalysts, pharmaceuticals are another targeted area for the new capacity.

BASF's position in amine production is part of its broader Verbund strategy, which seeks to take advantage of the company's backward integration in various chemical production streams. Its Verbund approach serves as the basis for its position in chiral intermediates, which is centered around four areas: chiral amines, chiral alcohols, chiral epoxides, and chiral hydroxy acids, all of which are used as building blocks in pharmaceutical manufacture.

BASF launches biocatalysis unit

Another addition to BASF's chiral toolbox is a biocatalysis service unit that offers screening, optimization, and biocatalyst fermentation up to 5 m³ , and scale-up from kilogram to ton-scale. "Biocatalysis has always been a part of our toolbox," says Frank Stein, director, new business development at BASF's intermediates group. "What we have now done is to formally launch that service to the pharmaceutical industry. These services are for process development or for scale-up and commercial manufacture of chiral pharma intermediates."

To enhance its position in biocatalysis, BASF signed in February a new pact with Diversa Corporation (San Diego, CA, www.diversa.com), which specializes in enzymatic approaches for chemical and protein-based drug development, under which Diversa will be responsible for the discovery and optimization of new enzymes for BASF. The pact expands on an existing relationship under which BASF licensed a proprietary enzyme from Diversa for the biocatalytic route to a chiral pharma intermediate. BASF also is partnered with Solvias AG (Basel, Switzerland, www.solvias.com) in homogenous chemocatalysis for asymmetric hydrogenation.

Solvias targets chemocatalysis

Solvias AG launched its first full-scale high-throughput screening (HTS) screening service for asymmetric homogenous hydrogenation in February. The HTS screening service has the capability to handle carbon monoxide, making it applicable to include carbonylation and hydroformylation screening. Solvias plans to extend its screening services for carbonylation by the fourth quarter of this year.

ChiralQuest launches new ligands

ChiralQuest Inc. (Monmouth Junction, NJ), a subsidiary of VioQuest Pharmaceuticals Inc. (Basking Ridge, NJ, www.vioquestpharm.com) recently made available new chiral ligands on a commercial scale for use in asymmetric hydrogenation.

ChiralQuest was founded in 2000 based on technology from Pennsylvania State University (University Park, PA, www.psu.edu) professor Xumu Zhang. He developed a toolbox of chiral phosphine ligands for catalytic asymmetric hydrogenations for use on a variety of substrates, some of which had been historically resistant to facile hydrogenation.

ChiralQuest has five commercially available catalyst ligands, including C3-TunePhos, a member of the atropisomeric aryl bisphosphine ligand family. This ligand is designed to provide improved enantioselectivities and catalytic abilities similar to the chiral ligand BINAP (2,2'-bis-diphenylphosphino)-1,1'-binaphthyl).

New on a commercial basis is the third-generation of P-chiral ligands, DuanPhos for the asymmetric hydrogenation of β-amino ketones to make β-hydroxyl-amines, β-acylamino acrylates to make β-amino acids, and for the hydrogenation of itaconic acids and their derivatives, explains Michael Cannarsa, general manager of ChiralQuest.

Last year, ChiralQuest opened a new 40,000-ft² pilot production facility in Jiashan, China, to provide chiral intermediates up to 100 kg. The Jiashan facility complements kilo-laboratory facilities in Monmouth Junction, New Jersey.

Chiral separations: developments in SMB liquid chromatography and SFC

Although asymmetric synthesis and synthesis from chiral pools are two widely used methods for obtaining single enantiomers,resolution by chromatography also may be used.Simulated moving-bed (SMB) liquid chromatography and supercritical fluid chromatography (SFC) are two approaches,and several companies are expanding.

SMB liquid chromatography

Ampac Fine Chemicals (AFC,Rancho Cordova,CA, www.apfc.com) is expanding in SMB liquid chromatography with the addition of a sixth SMB unit that came on line last month.The new 5 × 1000 mm unit is the largest SMB unit in North America,says Olivier Dapremont,AFC's chromatography specialist,business development. It can process about 200 metric tons of material per year depending on the productivity.AFC also has 8 × 200 mm and 6 × 800 mm SMB units that can process throughput as much as 100 metric tons.

SMB is used to separate enantiomers or other binary-like separations,explains Dapremont. In SMB, the sample is pumped continuously in a merry-go-round of columns and eluted.The two components (the two enantiomers in the case of a chiral separation) move at different speeds because of their respective interaction with the stationary phase and hence are separated.By using a sequence of valve activation,the countercurrent of the eluent and stationary phase is simulated,and the two compounds appear to be moving in two different directions,thus allowing for a continuous collection with high purity.

As with all chromatographic separations,a longer bed length improves the separation because additional equilibrium steps or theoretical plates are made available.Under SMB liquid chromatography,the bed length of the stationary phase that interacts with the feed mixture (i.e.,the racemic mixture in a chiral separation) is optimized using a countercurrent flow.As a result,a shorter bed length is required to achieve the separation and hence,flow rates can be increased to allow separation at maximum operating pressures, further increasing the throughput.

SMB is an established technique for enantiomeric resolution, and some recent advances center on the choice of the stationary phase.In a chiral separation, the stationary phase is based on materials that are the source for specific stereoselective interactions and then preferentially bind the different enantiomers.

The loading capacity of the stationary phase is an important factor that determines the productivity of the process and the associated economics of SMB compared with other chiral technologies such as asymmetric synthesis or a chiral pool synthesis.

For large-scale chiral preparations,derivatized polysaccharides are used for the stationary phase. To further improve SMB productivity,Chiral Technologies Inc.(West Chester,PA, www.chiraltech.com) introduced a line of immobilized polysaccharide stationary phases to supplement its original line of coated polysaccharides.By immobilizing the phase,the choice of solvents that can be used in liquid chromatography is expanded,resulting in higher solubility,increased selectivity,and higher loading capacity.

Supercritical fluid chromatography

SFC used with chiral stationary phases is another way to resolve enantiomers.With SFC,most of the liquid solvent is replaced by pressurized carbon dioxide,and only a small percentage of an organic solvent is required to solubilize the compound and serve as a co-solvent with the carbon dioxide.

Several companies are advancing SFC for chiral separations.Regis Technologies (Morton Grove,IL, www.registech.com) is adding a preparative-scale SFC unit in the third quarter 2006.The addition of the preparative-SFC unit will allow Regis to perform chiral and achiral separation on a standalone contract basis or in conjunction with its GMP manufacturing capabilities.Regis will serve as the Midwestern demonstration site for a working GMP SFC operation for Thar Technologies Inc. (Pittsburgh,PA, www.thartech.com). Regis also recently completed a SFC chiral application guide for 78 chiral separations.

Last month,Chiral Technologies introduced a new line of SFC chiral columns for analytical, semipreparative- and preparative-scale SFC separations.The SFC columns range from 4.6 mm ×100 mm for analytical method development through 5 cm × 25 cm as the largest size for preparative separations.

Chiral Technologies also has licensed chiral stationary phase technology from the University of Vienna based on work by Professor Wolfgang Lindne et al.The stationary phases are quinine and quinidine derivatives that have a tertiary amine in a binding cleft,along with additional hydrogenbonding sites,which make possible high-resolution separations of molecules with carboxylic, phosphonic,phosphoric,or sulfonic acid groups.

Western fine chemical companies position in India and China

Western custom manufacturers and fine chemical suppliers are adjusting to the rising competition of suppliers in India and China by partnering with offshore suppliers or setting up internal operations to take advantage of lower cost production economics.

Degussa AG (Düsseldorf, Germany, www.degussa.com) is the latest company to join the fray. Last month, Degussa signed a long-term, nonexclusive agreement with Hikal Ltd. (Mumbai, India, www.hikal.com) for the manufacturing of advanced intermediates and active pharmaceutical ingredients (APIs). Degussa will provide certain projects to Hikal, and Hikal will provide manufacturing of the respective advanced intermediates and APIs for Degussa.

Hikal is a custom manufacturer of APIs, intermediates, and crop protection products. It operates GMP manufacturing facilities in Mahad and Taloja in Maharashtra; Panoli in Gujarat; and an R&D center and an US Food and Drug Administration-approved API manufacturing facility in Bangalore.

"We have audited Hikal's facilities and found that its equipment, R&D capabilities and processes meet the rigorous requirements that we set for our own facilities," said Rudolf Hanko, vice- president of the exclusive business line at Degussa, in a company statement. " Together, with Degussa's first class R&D and manufacturing facilities in Europe and North America, we can now offer our customers a tailor-made cost mixture of Western and Asian facilities."

Hikal also is building a network of low-cost raw materials. In November 2005, it acquired a minority stake in one of the subsidiary companies of the Chinese chemical conglomerate Sinochem Corporation (Beijing, China, www.sinochem.com). The acquisition enables Hikal to backward integrate sourcing for some of its intermediates and APIs. Hikal had been sourcing intermediates from Sinochem for one of its products.

Hikal is building a new 140,000-ft² facility in Pune in western India to meet increasing demand for contract research services from pharma, biotech, and agrochemical companies, says Sareem Hiremath, Hikal's executive director.

Other custom manufacturers are following suit. For example, the large custom manufacturer Lonza AG (Basel, Switzerland, www.lonza.com) brought on line a new R&D center in Nansha, China in March. The new center is focused on process R&D for APIs and intermediates and houses 60 scientific personnel. Lonza's primary manufacturing and R&D operations for its exclusive synthesis business is in Visp, Switzerland.

JFC Technologies (Bound Brook, NJ, www.jfctechnologies.com) started up a new bulk pharmaceutical ingredient plant in Ningbo, China, in January. Reactor capacity for the new plant ranges from 2000 to 5000 L and is GMP-compliant under ICH Q7A guidelines. The China plant is JFC's first offshore facility. Its primary manufacturing facilities are in Bound Brook, NJ, where it has more than 50,000 L of reactor capacity with individual reactors ranging from 20 to 8000 L.

At the same time, Indian and Chinese producers continue to expand domestically as they also build their asset base offshore. For example, Dishman Pharmaceuticals & Chemicals Ltd. (Ahmedabad, India, www.dishmangroup.com) acquired I03S Ltd. (Bern, Switzerland, ww.io3s.com), a company specializing in ozone chemistry in February. In 2005, Dishman acquired the Manchester, UK-based contract research company Synprotec Ltd.

Dishman recently completed a new 75,000-ft² R&D center at its Bavla manufacturing site in Ahmedabad, India,which includes CGMP kilo and pilot plants. The facility has 270 m³ of reactor capacity. The company also expanded its facilities in Naroda, India, to include CGMP manufacture of quaternary ammonium and phosphonium compounds and certain bulk drugs.

These moves follow acquisitions of Western assets by Indian fine chemical producers. These include: Shasun Chemicals & Drugs Ltd.'s (Chennai, India, www.shasun.com) pending acquisition of Rhodia's pharmaceutical custom synthesis business; the 2005 acquisition of Avecia Pharmaceuticals by NPIL Pharma, the custom manufacturing arm of Nicholas Piramal India Ltd. (Mumbia, India, www.nicholaspiramal.com); and the 2005 acquisition of Novus Fine Chemicals by Malladi Drugs & Pharmaceuticals (Chennai, India, www.malladi.com). Novus is a producer of pseudoephedrine, phenylephedrine, and other APIs and is based in in Carlstadt, NJ.

Process R&D: C–N coupling reactions

Solvias AG (Basel, Switzerland, www.solvias.com) has advanced its role in chemocatalysis through a recent license agreement for carbon–nitrogen (C–N) coupling technology for aromatic and heteroaromatic chlorides, bromides, and sulfonate with amines and imines from Yale University.

The agreement centers around the use of Solvias'"Josiphos" ligand, a proprietary chiral ligand that is primarily used for asymmetric transformations such as hydrogenations, allylic alkylations, ring-opening reactions, Grignard additions to α, β-unsaturated ketones, and copper-catalyzed silane reductions.

The new licensing agreement extends the use of the ligand in Buchwald-Hartwig amination reactions (1, 2) a type of C–N coupling reaction. Solvias launched a new carbon–carbon—C–N coupling kit that it developed with the specialty materials company Umicore (Brussels, Belgium, www.umicore.com). Buchwald-Hartwig aminiation reactions are used in the pharmaceutical, agrochemical, and specialty chemical industries because they are high yielding and use relatively inexpensive starting materials such as primary and secondary amines or imines, aryl halides, and sulfonates.

References

1. J.F. Hartwig et al. "Highly Reactive, General, and Long-Lived Catalysts for Coupling Heteroaryl and Aryl Chlorides with Primary Nitrogen Nucleophiles," Angew. Chem. Int. Ed. 44 (9), 1371 (2005).

2. A.H. Roy and J.F. Hartwig, "Oxidative Addition of Aryl Tosylates to Palladium(0) and Coupling of Unactivated Aryl Tosylates at Room Temperature.," J. Am Chem. Soc . 125 (29), 8704 (2003).