Advancing Small-Molecule Synthesis

April 2, 2011
Patricia Van Arnum
Pharmaceutical Technology
Volume 35, Issue 4

Chemocatalytic and biocatalytic routes play an important role in improving the manufacture of intermediates and active pharmaceutical ingredients.

Catalysis plays a crucial role in small-molecule synthesis, whether it is in making an intermediate or the final active pharmaceutical ingredient (API). The effective development and application of a catalyst system can improve reaction conditions, yield, and optical purity as well as produce more efficient chemical transformations. As recent developments show, chemocatalysis and biocatalysis continue to be an active area of academic research and business investments.

IMAGE: MIRIAM MASLO/SPL, GETTY IMAGES

Advances from academia

Oxidative enamine catalysis. Researchers at the East China University of Science and Technology, the Shanghai Institute of Materia Medica, and the University of New Mexico recently reported on a new chemical transformation, oxidative enamine catalysis, a potentially valuable approach in synthesizing chiral intermediates. The researchers noted that although iminium catalysis, which involves the transformation of iminium ions to enamines, has been extensively studied, the reverse process, converting enamines to iminium species, has not been well examined. In their work, the researchers described oxidative enamine catalysis, or the direct oxidation of an enamine, to produce an iminium species. The researchers showed that the use of o-iodoxybenzoic acid as an oxidant in the presence of a secondary amine catalyst is an effective system for converting enamines to iminium ions. The work was carried out for the direct asymmetric -functionalization of simple aldehydes. The research was used in other enantioselective cascade transformations, including triple and quadruple cascades, for a one-pot synthesis of chiral building blocks and structural frameworks that begin with aldehydes (1, 2).

Patricia Van Arnum

Light-driven molecular motors in asymmetric reactions. Researchers at the University of Groningen in The Netherlands recently reported on a light-driven molecular motor with a switchable catalytic function in catalytic asymmetric reactions. Specifically, the researchers reported on a light-driven molecular motor with integrated catalytic functions in which the stepwise change in the configuration during a 360° unidirectional rotary cycle dictated the catalyst performance with respect to activity and absolute stereocontrol. During one full rotary cycle, catalysts were formed that produced either racemic (R, S) or preferentially the R or the S enantiomer of the chiral product of a conjugate addition reaction. The researchers noted that insitu switching of the chiral preference of a catalytic system had been difficult to achieve. The catalytic system in their work showed that different molecular tasks can be performed in a sequential manner and the sequence was controlled by the directionality of the rotary cycle (3, 4).

Palladium-catalyzed reactions. A research team, lead by Stephen Buchwald, professor of chemistry at the Massachusetts Institute of Technology (MIT), reported on a new way to attach a trifluoromethyl group to certain compounds, which has important implications for pharmaceutical compounds. A trifluoromethyl group may be attached to a pharmaceutical compound as a strategy to prevent the drug from breaking down too rapidly in the body. The trifluoromethyl group is a component of several drugs, including the antidepressant Prozac (fluoxetine hydrochloride) by Eli Lilly, the arthritis medication Celebrex (celecoxib) by Pfizer, and the antidiabetes drug Januvia (sitagliptin phosphate) by Merck & Co., according to a June 24, 2010, MIT press release.

According to the MIT researchers, no general method existed for installing trifluoromethyl groups onto functionalized aromatic substrates. Commonly used methods either required the use of harsh reaction conditions or had limited substrate scope. In their work, the researchers reported on the palladium-catalyzed trifluoromethylation of aryl chlorides under mild conditions to permit transformation of various substrates, including heterocycles. The process tolerated functional groups, such as esters, amides, ethers, acetals, nitriles, and tertiary amines, thereby making them useful for late-stage modifications of advanced intermediates (5). An important component to the palladium-based catalyst system was the BrettPhos ligand, a biarylmonophosphine ligand. During the reaction, a trifluoromethyl group was transferred from a silicon carrier to the palladium, displacing a chlorine atom. Subsequently, the aryl–trifluoromethyl unit was released, and the catalytic cycle began. The researchers tried the synthesis with various aryl compounds and achieved yields ranging from 70 to 94% of the trifluoromethylated products, according to the MIT release.

Buchwald previously reported on the BrettPhos ligand in a catalyst system for carbon–nitrogen cross-coupling reactions. The system enabled the use of aryl mesylates as a coupling partner in carbon–nitrogen bond-forming reactions. He and his research team reported on the use of the BrettPhos ligand in a catalyst system to achieve the selective monoarylation of various primary aliphatic amines and anilines at low catalyst loadings with fast reaction times, including the monoarylation of methylamine (6).

Biocatalytic route to simvastatin. Researchers at the University of California Los Angeles (UCLA) recently reported on a biocatalytic route to simvastatin, the active ingredient in Merck & Co.'s anticholesterol drug, Zocor and also now off patent as a generic drug (7, 8). Simvastatin is a semisynthetic derivative of lovastatin. Adding a methyl group to convert lovastatin into simvastatin requires a multistep chemical synthesis that includes protecting and deprotecting other functionalities in the lovastatin molecule. In one process route, lovastatin is hydrolyzed to the triol, monacolin J, followed by protection by selective silylation, esterification with dimethyl butyryl chloride, and deprotection (7). Another route involves protection of the carboxylic acid and alcohol functionalities, followed by methylation with methyl iodide and deprotection. Both routes had less than 70% percent overall yield. The UCLA researchers developed an improved biocatalytic route based on directed evolution of the biocatalyst (7).

The researchers first cloned and identified LovD, a natural acyltransferase in Aspergillus terreus, which is involved in the synthesis of lovastatin and can accept nonnatural acyl donors. LovD converts the inactive monacolin J acid into lovastatin. LovD can also synthesize simvastatin using monacolin J acid and a synthetic a-dimethylbutyryl thioester although with less-than optimal properties as a biocatalyst. The researchers used directed evolution to improve the properties of LovD toward a semisynthetic route of simvastatin. Mutants with improved catalytic efficiency, solubility, and thermal stability were obtained, with the best mutant displaying an approximate 11-fold increase in an Escherichia coli-based biocatalytic system (7, 8).

Business developments

Catalysis, both chemocatalysis and biocatalysis, is an active area of investment of fine-chemical companies, contract manufacturers, and technology providers specializing in catalysis. In March 2011, Materia announced plans for a catalyst manufacturing and research and development facility in Singapore. Materia specializes in olefin-metathesis catalyst technology based on the work of Robert Grubbs, professor at the California Institute of Technology, the 2005 Nobel Laureate for Chemistry, and a member of Materia's scientific advisory board and board of directors. Olefin-metathesis technology is used in fine-chemical manufacture and in other industrial chemical sectors.

Materia expects to complete the site-selection process in the third quarter of 2011 and begin construction by the end of the year. The facility will have initial operating capacity of 10 metric tons by the end of 2012. In addition to catalyst manufacturing, the plant will house research, development, and technical-service resources. Earlier this year, Materia received a $17-million investment by a group of private investors.

The contract development and manufacturing organization (CDMO) Almac is expanding its biocatalysis business with a $4-million investment for discovering new biocatalytic platforms and for other research areas. These areas include hyperactivation of biocatalysts to reduce enzyme loadings, drivers for cofactor recycles, and resolving problems with equilibriums. In 2009, Almac launched carbonyl reductase, transaminase, hydrolase, nitrilase, and nitrile hydratase enzyme-screening kits. In adddition to screening kits, the company offers services for enzyme-screening kits and custom transformations, and supply of chiral intermediates.

In January 2011, Codexis formed a biocatalysis collaboration with Dainippon Sumitomo Pharma (DSP). Under the agreement, Codexis is supplying biocatalysis-screening products and services to DSP for use in selected undisclosed therapeutic products in DSP's development pipeline. Also, in January 2011, Codexis and DSM Pharmaceutical Products, the custom-manufacturing organization of Royal DSM, formed an enzyme-supply agreement. The agreement grants DSM rights to use Codexis' custom biocatalysts and services and secures supply of Codexis enzymes for commercialization of pharmaceutical manufacturing routes developed by the InnoSyn route-scouting services of DSM. In early 2010, Codexis formed two separate pacts for applying its biocatalyst technology for two other CDMOs, Ampac Fine Chemicals and Dishman Chemical and Pharmaceuticals, for their use in manufacturing intermediates and APIs.

Codexis recently worked with Merck & Co. to develop an enzymatic process to make sitagliptin, which is the active ingredient in Merck's Januvia. The process improvements in the sitagliptin synthesis were recognized by the US Environmental Protection Agency's 2010 Presidential Green Chemistry Challenge Awards. The earlier manufacturing process involved an asymmetric catalytic hydrogenation of an unprotected enamine, but had some challenges, including inadequate stereoselectivity that required a crystallization step and high-pressure hydrogenation (at 250 psi) that required the use of a rhodium catalyst (7).

Collaboration between Merck and Codexis led to an improved, greener route for the manufacture of sitagliptin. Starting from an R-selective transaminase, with some slight activity on a smaller, truncated methyl ketone analog of the sitagliptin ketone, Codexis evolved a biocatalyst to enable a new manufacturing process to supplant the hydrogenation route. The evolved transaminase had a compounded improvement in biocatalytic activity of more than 25,000-fold, with no detectable amounts of the undesired, S-enantiomer of sitagliptin being formed. The streamlined, enzymatic process eliminated the high-pressure hydrogenation, metal catalysts (i.e., rhodium and iron), and the chiral purification step. The benefits of the new process included a 56% improvement in productivity, a 10–13% overall increase in yield, and a 19% reduction in overall waste generation (7).

In October 2010, Codexis expanded its portfolio of screening kits to include two commonly used enzyme classes, ketoreductase and transaminase enzymes. The company also entered its panels for ketoreductase biocatalysts for producing chiral secondary alcohols, which are used as intermediates in asymmetric API synthesis, for consideration in EPA's 2010 green chemistry awards. Codexis developed processes for chiral alcohol intermediates of four generic APIs with variants identified from its KRED (i.e., ketoreductase) panel screens. Codexis also has other enzyme panels of transaminase, nitrilase, acylase, halohydrin dehalogenase, and "ene" reductase biocatalysts.

Johnson Matthey recently integrated its biocatalyst offerings from X-Zyme, which Johnson Matthey acquired in July 2010. Johnson Matthey expanded the biocatalyst offerings into product and service offerings in its catalysis and chiral-technologies businesses. The portfolio from X-Zyme includes enzymatic catalysts for scalable production of highly pure chiral amines and alcohols. The biocatalysts and related technology complement the chemocatalytic technology and related expertise of Johnson Matthey. Also, in March 2010, the CDMO Cambrex acquired IEP, a technology company located in Wiesbaden, Germany, to build its portfolio for offering customized biocatalytic process development and sales of enzymes to the pharmaceutical industry.

Among pharmaceutical companies, Pfizer recently highlighted some improvements in API manufacturing routes, which included developing a biocatalytic route for pregabalin, the API in the pain treatment Lyrica (7, 9). A biocatalytic route and other green-chemistry improvements resulted in reducing solvent use by 5 million gallons per year and eliminating more than 150 tons of a nickel catalyst by using a third-generation synthesis in the manufacture of pregabalin. Other process improvements in other API manufacture involved a reduction by 65% of the total organic waste (3.5 million liters per year of methanol and tetrahydrofuran) and the elimination of liquid nitrogen in one step in manufacturing atorvastatin, the API in Pfizer's Lipitor. The company also eliminated 25,000 tons of waste per year in the manufacture of voricanazole, the API in Vfend through a green-chemistry modification in the manufacturing process. The synthesis used two innovative types of chemistry: an ultra-efficient synthesis of the key pyrimidinone intermediate and the development of a novel highly diastereoselective Reformatksy coupling reaction (9).

In general process improvements, Sigma-Aldrich recently reported on a route for manufacturing polyamino acids, which have properties that mimic proteins, thereby making them suitable for targeted drug delivery. Their production involves the intermediate amino acid N-carboxyanhydrides (NCAs) and polymer processing. For NCA production, the company eliminated repeated NCA recrystallizations and minimized manufacturing runs by 30%, and reduced the use of phosgene and tetrahydrofuran by 30% and ethyl acetate and hexane by 50% (7).

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, pvanarnum@advanstar.com.

References

1. S.L. Zhang et al., Nat. Comm., DOI:10.1038/ncomms1214, Mar. 1, 2011.

2. S. Borman, Chem. & Eng. News 89 (10), 9 (2011).

3. J. Wang and B.L. Feringa, Science 331 (6023), 1429–1432 (2011).

4. B. Halford, Chem. & Eng. News 89 (7), 9 (2011).

5. E.J. Cho et al., Science 328 (5986), 1679–1681 (2010).

6. S. Buchwald et al., J. Am. Chem. Soc. 130 (41), pp 13552–13554 (2008).

7. EPA, The Presidential United States Environmental Protection Agency Green Chemistry Challenge Agency Awards Program Summary of 2010 Award Entries and Recipients (Washington DC, 2010).

8. Y. Tang et al., Chem. Biol. 16 (10), 1064–1074 (2009).

9. B. Kovats and K.Ball, Pharm. Technol. 33 (9), online exclusive (2009), pharmtech.findpharma.com/pharmtech/article/articleDetail.jsp?id=624208&pageID=1&sk=&date=, accessed Mar. 15, 2011.