COVER STORY
CENTERING ON CHIRALITY Chemists are finding ASYMMETRIC SYNTHESIS increasingly handy for making pharmaceutical compounds at large scale ANN M. THAYER, C&EN HOUSTON
NATURE HAS A WAY OF KNOWING how to make things work. Reactions often run in a catalytic mode, and material use, energy, and waste are minimized. Many molecules are chiral, and their unique handedness has both intricate and dramatic influences on how they interact with biological systems. In pharmaceuticals, stereoselective interactions are profoundly important because one or the other IN THE POCKET enantiomer of a com- Metal-binding pocket of a pound can have bendiazaphospholane eficial or disastrous ligand, with the results. Awareness two phosphorus atoms in gold, of this phenomenon that has been intensified when the found effective teratogenic effects of for asymmetric thalidomide, once hydroformylation.
used as an antinausea drug for pregnant women, emerged in the 1960s. Thalidomide and many other chiral drugs had been sold for years as racemic mixtures. In 1992, the U.S. Food & Drug Administration issued a policy on stereoisomeric drugs. Racemates can be sold—FDA still occasionally approves them, and even thalidomide is now used with appropriate warnings in chemotherapy—but the enantiomers must be characterized pharmacologically and toxicologically. Since one enantiomer could be unsafe or merely inactive baggage, and the cost of characterization is so high, the drug industry has shifted to making single-enantiomer forms of chiral compounds. "In 2006,80% of ( small-molecule
MORE ONLINE WWW.CEN-0NLINE.ORG
drugs approved by FDA were chiral and 75% were single enantiomers," says Ian C. Lennon, scientist and technology leader for Dowpharma. Assuming no differences between chiral and achiral compounds in their discovery, attrition, or approval rates, about 200 chiral compounds could enter the development process each year. To meet these challenges, chemists in the pharmaceutical industry are increasingly called upon to mimic what nature does so easily and so well. They may try a variety of chiral technologies, including separations, salt resolutions, and asymmetric syntheses involving chiral auxiliaries, chemocatalysis, or biocatalysis to get to a single enantiomer. Or they may start with building blocks, when available in sufficient quantity and quality at the right price, from the chiral pool. The field of asymmetric synthesis is expanding rapidly. Academic researchers continually create new reactions or asymmetric variants of existing ones. Within industry, process chemists must adapt these to production needs to make single-enantiomer compounds practically and efficiently at large scale in extremely high purity. Process chemists usually step in to make initial kilogram amounts of an active pharmaceutical ingredient (API) for preclinical and early clinical work. "This is the only stage during the entire drug discovery and development process where simply making the API is on the critical path between discovery and marketing a new drug," explains Karel M. J. Brands, a senior director in the process research department at Merck. "Speed is essential, and you don't always have the luxury of trying to come up with the best synthesis."
Read more about how university researchers are advancing asymmetric synthesis at C&EN Online, www.cen-online.org. ]_]_
AUGUST 6. 2007
COVER STORY
As a starting point, these chem ists are frequently inspired by the medicinal chemistry route, he ex plains. These routes, however, are seldom practical and efficient—or environmentally benign and eco nomically viable. Instead, they may use undesirable or hazard ous reagents to make racemates, followed by chromatography to separate enantiomers. "The deliberate design of an asymmetric synthesis comes later," Brands says, when the drug candidate is ready to move into early proof-of-concept studies. "This is when a molecule starts to become of serious interest, and we are willing to put some signifi cant resources into coming up with the best possible synthesis." Other routes maybe developed in parallel. "Most often at Merck, the arrival of the asymmetric synthesis comes in time to answer the much bigger scale needs for the late development of an API," he says. "To have a fundamentally ef ficient approach to a chiral target, you have to practice asymmetric chemistry." In the early 1990s, most chiral drugs were derived from chiral-pool materials, and only 20% of all drugs were made via purely synthetic approaches, Lennon says. "Today, just 25% come from the chiral pool and over 50% use chiral technologies." "Asymmetric synthesis is still seen as very challenging," says Hans-Jurgen Federsel, director of science in global process R&D at AstraZeneca. "Much of it relies on catalysis, and designing a catalytic process and ensuring it operates well takes a lot of time." Outcomes are unpredictable, and because many APIs and intermediates are
Chemwx • • • •
_
VIABLE OPTIONS As an alternative to a chiral auxiliary-based route (top), Sepracor chemists developed an asymmetric synthesis (bottom).
unprecedented as substrates, it can be dif ficult to even know where to begin, he adds. "Many people in the pharmaceutical in dustry don't want to take on that burden," Federsel says. "Why invest a lot of effort in designing a fantastic process if you will have to discontinue it a year down the line because of the compound's toxicity or lack of efficacy?" Time and cost pressures, along with the quantity of projects, often dictate that other processes will win out. "Quick methods, and preferably generic ones, are desirable to cut out as much de velopment work as possible," he says. "Preparative chromatography is now blooming. This was always seen as a last re sort but has now been integrated into nor mal project work to a much higher degree," Federsel continues. "Even if it is expensive, we know that it works and that within a few
Keypad Programmable
Graphical User Interface Imbedded Syringe Library Broad Flow Range Run-time Status With Stall Detection & Alarm
Syringe Size: 10 μΙ - 60 ml each Dimensions: 9.6 χ 6.5 χ 4.5 in Min. Flow Rate (10 μΙ syringe) 0.001 μΙ/hr Max. Flow Rate (60 ml syringe) 90 ml/min
WWW.CEN-0NLINE.ORG
]_2
AUGUST 6, 2007
days, we can produce a couple kilograms to drive a project forward." Many company scientists say a problem with using separations for large-scale pro duction is that the costs of making both enantiomers are incurred, but one will be discarded. Higher yields maybe possible if the second enantiomer can be converted or racemized for reprocessing. On the plus side, chiral chromatography is applicable to most chiral small molecules and is very scalable. Several drugs have been made this way at the multiton scale, includ ing Pfizer's antidepressant Zoloft, UCB Pharma's epilepsy drug Keppra, Cephalon's insomnia drug Nuvigil, and Lundbeck's Cipralex, also marketed by Forest Laboratories as Lexapro, for depression. "Existing commercial projects have demonstrated that it is often cheaper to produce single-enantiomer drugs with chromatography than with traditional technologies such as crystallization or asymmetric synthesis," Jean Blehaut, pres ident of Novasep's pharma business unit, said in June when announcing a collabora tion with Daicel Chemical Industries. The two companies have partnered to promote the use of chiral chromatography for pro ducing intermediates and APIs. Traditional methods for crystallizing diastereomeric salts have found wide use. Gipralex (escitalopram) is the S-enantiomer of the earlier racemic drug Celexa. Several resolutions have been published, a recent one using didesmethylcitalopram. Chemists at Dr. Reddy's Laboratories and
ChemBridge's GPCR Library collaborators in India took the somewhat unusual approach of chemically modifying a chiral amine handle on the substrate itself to improve a salt resolution (Org. Process Res. Dev. 2007,11,289). Although salt resolutions require a lot of trial and error, they are usually easy to handle and simple to scale up, says Vijayavitthal T. Mathad, who moved from Dr. Reddy's to Megafine Pharma, in Mumbai, where he is vice president of R&D. "The cost of resolution processes is normally affordable, even by a small manufacturer," he adds. Solvents and inexpensive resolving agents are recoverable at high levels. Cost and time pressures may rule out exploring asymmetric synthesis, he adds, especially in the competitive generic drug market. Scientists at Dr. Reddy's and collaborators also came up with a less expensive alternative resolution route to make an intermediate for aprepitant, the API in Merck's antiemetic drug, Emend (Org. Process Res. Dev. 2007,11,455). They targeted the morpholine core that has two of the drug's three chiral centers. Another aprepitant intermediate bearing a third chiral center is (iR)-[3,5-bis(trifluoromethyl) phenyl] ethanol(BTMP). The Dr. Reddy's team enantioselectively transesterified the racemic alcohol using vinyl acetate as the acyl donor and a lipase enzyme. This resolved the unacylated Salcohol and R-acetate, which was hydrolyzed separately to the R-alcohol. Swiss catalyst developer Solvias and its scale-up partner Novasep have published an asymmetric route they developed in just two months to produce BTMP for Merck using a ruthenium catalyst with a chiral phosphineoxazoline ferrocenyl ligand (Org. Process Res. Dev. 2007,11,519). The route involves the enantioselective hydrogénation of 3,5bis (trifluoromethyl) acetophenone. "The enantioselective reduction of aryl ketones is an important transformation from both academic/synthetic as well as industrial points of view," they write. They ran their optimized process twice on a 140kg scale, finding it could compete with alternatives such as transfer hydrogénation and biocatalytic and hydride reductions. "More and more pharmaceutical companies are comfortable using asymmetric hydrogénation, although a few haven't tried it yet," Dowpharma's Lennon says. Although the technology has been around for decades, in the past five years, publications, catalysts for testing, substrates tested, suppliers, and success sto-
ries have helped it move into API synthesis. Four drugs approved in just the past 24 months—Takeda's Rozerem (ramelteon), a sleep aid that binds to melatonin receptors; Merck's Januvia (sitagliptin), one of a new class of oral diabetes drugs; Novartis' Tekturna (aliskiren), the first hypertension drug to target the kidney enzyme renin; and Boehringer Ingelheim's Aptivus (tipranavir), an HIV protease inhibitor—have chiral centers reportedly generated via catalytic asymmetric hydrogénation. That hydrogénation is the final synthesis step for the first two drugs is surprising, Lennon remarks. Concerns about hydrogenating valuable complex molecules and catalysts contaminating the final product made such routes almost unthinkable a few years ago (C&EN, Sept. 5,2005, page 55). Now, Merck makes multiple tons of the chiral β-amino acid derivative sitagliptin via the late-stage hydrogénation of an unprotected enamine, using a rhodium catalyst and the Solvias chiral ligand Josiphos. The manufacturing processes for Emend and Januvia, in large part because of their innovative use of asymmetric synthesis, won Presidential Green Chemistry Challenge Awards, Merck's Brands notes. Merck has validated catalytic approaches many times. It got a leg up on the competition by deciding a few years ago to have a lab dedicated to discovering and developing asymmetric hydrogénations. "Within a matter of days, we can find a solid hit and systematically work our way to something that can be scaled up," Brands says.
A Preferred Resource for Difficult Targets
ALONG THESE LINES, Merck Associate Director Kevin R. Campos discussed process development for taranabant at Scientific Update's Modern Synthetic Methods & Chiral USA meeting in Philadelphia last month. Now in Phase III clinical trials, the antiobesity agent blocks endocannabinoid receptors to control hunger and is a potential competitor to Sanofi-Aventis' rimonabant. Taranabant is a hindered secondary amine with two contiguous stereocenters. In lieu of a nine-step medicinal chemistry route that used expensive and toxic materials, as well as chiral chromatography, the process group developed a dynamic kinetic resolution based on enantioselective catalytic reduction to convert a racemic ketone starting material into a single enantiomer of the corresponding alcohol in high yield (Org. Process Res. Dev. 2007, n> 616). By this means, they produced 65 kg of material, despite it requiring azide
* Designed to enable rapid hit-to-lead
ln-house Validation: Targeted Library vs. Diverse Library MC-4 Hit statistics versus ECS0 (μΜ) for 10,000 compounds GPCR Library
Control - Diverse Library
Meianocortin-4 Cell-Based Agonist Screening Experimental Results: Diverse Control: 5 weak hits «10,000 compounds randomly selected from the ChemBridge GPCR targeted library screened at 10μΜ
» 10,000 compounds from a similar 'control' diversity library screened under identical conditions
GPCR Library Properties: * Comprised of >10 unpublished 'preferred templates' mimicking beta-turns, and using in-house building blocks, culminating from a four year R&D effort * Over 15,000 drug-like, highly pure, small molecule compounds « Successful identification of both agonists and antagonists * Drug discovery advancements by several Independent laboratories
WWW.CEN-0NLINE.ORG
12
AUGUST 6, 2007
optimization with quick follow-up in medicinal chemistry services
Client Statement "We are very pleased with the quality of the ChemBridge GPCR-focused library, particularly since the library helped us to resurrect several projects that we had previously dropped due to lack of leads." Jeremy Caldwell, Ph.D. Director of Molecular and Cellular Biology Genomics Institute of the Novartis Research Foundation
fj: Please contaptl|^S ^ales@ChemBridg|l||e a^fwv^chembridgej|c|^
COVER STORY
chemistry and work to upgrade the enantiopurity. The route also lacked solid intermediates, which limited options for production. "The chemistry is varied, and the vendors who specialize in transition-metal chemistry are not versed in handling azides and vice versa," Campos tells C&EN. "The lack of solid intermediates prevented us from transferring between vendors." Campos and coworkers then created a route involving the stereocontrolled formation of a tetrasubstituted enamide. It relies on a Merck-developed palladiumcatalyzed coupling to make the enamide (Org. Lett. 2005,7,1185). Rhodium-catalyzed asymmetric hydrogénation of the enamide, using a Solvias ligand, forms both chiral centers in a single step. "We had to be innovative with the chemistry because no examples of asymmetric hydrogénation of tetrasubstituted enamides of this complexity are in the literature, especially ones that have been performed on a multikilogram scale," Campos says. "Even though the substrate is complex, the synthesis is con-
génation product crystallizes with an upgrade to 99% ee. Because the cyanoenamide couldn't be directly hydrogenated, the process required two extra steps to hydrolyze the cyano group and then convert it back. A Roche team recently published a new enantioselective synthesis of or1. Hydrolysis listat, the API in the antiobesity drug 2. Hydrogénation Xenical, designed to decrease fat absorp3. Dehydration tion. Using a ruthenium-MeOBIPHEP catalyst, they hydrogenated a β-ketoester in the first step to create a critical enantiopure intermediate (Org. Process Res. Dev. 2007,11,524). They have pro duced more than two tons of the. result ing β-hydroxyester at over 99% ee. The ligand is from a family of atropisomeric EASY AS 1-2-3 diphosphines invented at Roche and Asymmetric hydrogénation used in several large-scale processes. of a tetrasubstituted Solvias has licensed this ligand fam enamide completes Merck's synthesis of taranabant. ily and makes it and other asymmetric hydrogénation catalysts available for screening and at large scale. Dowpharma vergent, and the chemistry is quite robust." makes more than 10 at kilogram scale, inThe route takes six steps with 54% yield cluding Me-DuPhos, which is used in the and 96% enantiomeric excess (ee). Every production of several major drugs. Chiral intermediate is isolatable, and the hydro-
Fast, Unambiguous Absolute Configuration Determination... No Crystallization. No Derivatization.
Discover VCD! BioTools 'Toole for Discoveries
of Life*
950 N. Rand Rd. Suite 123, Wauconda, IL 60084; Tel: (847) 487-5500; Toll Free (866) BTOOLS1 ; Fax: (847) 487-5544 Web: www.btools.com; Email:
[email protected] WWW.CEN-0NLINE.ORG
\A
AUGUST 6, 2007
Quest has commercialized five catalysts, some of which are being used in large-scale development projects. Other suppliers working in this area are DSM, Degussa, Takasago International, and Johnson Matthey. Benoit Pugin, a lead scientist at Solvias, estimates that more than 3,000 chiral diphosphine ligands are known. Reasons behind the diversity are their substrate specificity and the empirical means by which they are selected and employed. Only about 5-10% of the ligands are commercially available in small quantities, and just about 1% in kilogram quantities, he says. Making larger amounts can be done by devising easy and scalable syntheses. Along these lines, Solvias has designed newferrocenyl ligands, including P-chiral ligands called Ghenphos. This class was designed to compete with Trifer catalysts from Phoenix Chemical's Stylacats unit (Angew. Chem. Int. Ed. 2007,46,4141) and DSM's MonoPhos catalysts in making Novartis's Tekturna. Among several known routes to the drug, two in production depend on catalytic asymmetric hydrogénation. A process developed by Speedel Pharmaceuticals in close collaboration with Solvias uses Solvias' Walphos. DSM scientists recently reported their mixed-ligand approach using a chiral phosphoramidite and nonchiral triarylphosphine to increase the rate and enantioselectivity (Org. Process Res. Dev. 2007, iiy 585). At the Philadelphia meeting, Pugin showed that Chenphos offers even better productivity and enantioselectivity. WITH THE EXPANSION in chiral ligand libraries, some companies have partnered with outside specialists to introduce catalytic asymmetric processes at an early point in development. An example is Eli Lilly & Co.'s chemical product R&D group, which sought an improved route to a selective estrogen receptor β agonist for prostatic disease. At the meeting, research adviser Scott A. May discussed Lilly's efforts to develop an effi cient route to a substituted benzopyran with three contiguous chiral centers. Lilly's three-pronged assault on the ste reochemistry played to its own and others' strengths. Internally, they screened clas sical and enzymatic resolutions. Outside providers screened metal-ligand complex es on ester and carboxylic acid versions of a challenging tetrasubstituted alkene intermediate. In the end, Lilly decided to work with an outside provider to optimize a ruthenium P-Phos complex for asymmet
ric hydrogénation. And Lilly conducted the pilot-plant-scale process. In another collaboration, Dowpharma helped develop a route for Pfizer's Celsentri (maraviroc) and related backup compounds. In Phase III trials, the drug targets how HIV infects immune system cells, rather than the virus itself. U.S. and European approvals are expected this year. The
collaborators succeeded in synthesizing a preferred aldehyde-enamide intermediate and asymmetrically hydrogenating it. Making enamide substrates for asymmetric hydrogénation with a wide range of catalysts has become increasingly common. Scientists at Sepracor have developed large-scale stereoselective syntheses of (i#,4S)-£rafts-norsertraline hydrochloride,
solvias.
•&?&&>
High-Throughput Catalysis Screening Benefits
Features
• High success rate
• 96-well-plates, 192 experiments/day
• Rapid results • Comprehensive screening
• Up to 100 bar (H2, CO)
• Maximizes lead identification
• Fully integrated from DoE
• Minimizes substrate requirements
to analysis • Symyx technologies platform
Integrated Services
HTS Technologies
• Catalysis process optimization
• Asymmetric hydrogénation
and scale-up
• CX-coupling
• Catalyst and ligand supply by Solvias
• Carbonylation
• Route evaluation and redesign
Solvias Inc., 2125 Center Avenue Suite 500, Fort Lee, New Jersey 07024, USA Phone +1 201 302 6084, Fax +1 201 302 60 62,
[email protected], www.solvias.com
WWW.CEN-0NLINE.ORG
1C
AUGUST 6, 2007
• Bulk Supplier • Best Prices
· In S t o c k
'NH2
B—CH3 H O
HOOC
Methylboronic acid
"
' B(OH)2
3-Carboxyphenyiboronic acid
A
A
M
' / NH2HCI
c
H2 VNH2HCI
Trans-2-Aminocyclohexanol hydrochloride Trans-2-Benzyloxycyclohexylamine hydrochloride Both enantiomers are available.
And More..
&D?
Tel: 86-411-87549848 Fax: 86-411-87549748 E-mail:
[email protected] www.allychem.com A L L Y C H E M CO., LTD. DALIAN, CHINA
acamas laboratories
P.O. Box 17659 3625 N. Suttle Rd. Portland, OR 97217
Phone (503) 285-0360 Fax (503) 289-1355
www.lacamaslaboratories.com
a chiral amine structurally similar to the antidepressant Zoloft but with a different pharmacological profile. One challenge was establishing two chiral centers while overcoming a substrate bias toward forming the cis diastereomer. Their first approach, used to produce kilograms of material for clinical study, began with (S)-tetralone, which already contains one of the two needed chiral centers. Condensation with (R)-tert-butylsulfinamide (TBSA), which acts as a chiral directing group to dictate stereochemistry, leads to a sulfmyl imine that can be stereoselectively reduced and then hydrolyzed to the product (Org. Process Res. Dev. 2007, n> 7 2 6). "This synthesis was very quick to develop and scale up, which is why chiral reagents or resolutions are among the first processes we lean toward," says Roger P. Bakale, Sepracor's executive director for chemical process R&D. Looking for an alternative H E L P I N G H A N D An aminoindanol-based chiral to using expensive (R)-TBSA, a auxiliary directs the stereochemistry in Boehringer Sepracor team began scouting Ingelheim's asymmetric acetate aldol reaction. for other routes starting with the benzylic ketone tetralone. "Not that many asymmetric syntheses are "An obvious approach is the asymmetric used at large scale," he points out, "and we hydrogénation of an enamide, but there are feel good that we could do it." not many published procedures for making enamides from benzylic ketones," explains Although catalyst producers and many research fellow Surendra P. Singh. process chemists consider hydrogénation to be among the more mature methods in Instead, Singh and coworkers tackled asymmetric synthesis, it's not yet routine. a novel non-metal-based route to the enAnd, Dowpharma's Lennon cautions, amide. After succeeding, they worked with "asymmetric hydrogénation doesn't make Dowpharma and found an efficient Nora process by itself. It's effective only if the phos rhodium catalyst for the hydrogénawhole process is effective." tion. They then came up with a convenient Hydrogénations of functionalized oleprocess to deprotect the amide without fins and ketones are probably the easier racemization and yield the amine. asymmetric transformations to do, Merck's "We've scaled it up to make more than Brands explains, whereas catalytic asym50 kg of the API," Singh says. Details will metric carbon-carbon bond formation in appear in patents and publications. For a truly economic fashion is much more now, Singh says, the result is a short and difficult. New synthetic approaches will scalable process with an overall yield of gradually be adopted and should become 63% from the ketone. Besides the novel apparent as drug candidates advance. At chemistries, it uses an unpatented catalyst the same time, because attrition is so high, to give the product in 97% diastereomeric many processes will never be demonstratexcess (de) and 99.9% de after crystallization. ed on a manufacturing scale. Singh is proud that a smaller drug com"Outside of hydrogénation, no other pany team with limited resources created form of asymmetric catalysis is being broadthe norsertraline process from scratch. w w w . CEN-0NLINE.ORG
\ β
AUGUST 6, 2007
COVER STORY
ly applied at large scale," Lennon adds. Dowpharma is optimistic that hydroformylation will be next, and it is developing achiral and chiral ligands. The atom-efficient reaction combines an olefin, hydrogen, and carbon monoxide to form an aldehyde, which is a useful synthetic building block. THE COMPANY has worked with University of Wisconsin, Madison, chemistry professor Clark R. Landis, who has developed stable and active diazaphospholane ligands for enantioselective hydroformylation. The ligands can be easily synthesized from inexpensive starting materials and resolved to give both useful antipodes. They tolerate a range of functional groups to alter steric and electronic properties and offer practical enantioselectivities for a wide variety of substrates. Asymmetric hydroformylation can present challenges around chemo-, enantio-, and regioselectivity, as well as catalyst stability and reactivity. But the situation is improving. "There are fewer technical hurdles than business ones," says Robert B. Appell, technical sales and process R&D leader at Dowpharma. "Companies don't want to be beta testers and would like to see large-scale examples before they buy in." He says some are showing interest in catalyst screening. Hydroformylation requires different retrosynthetic thinking about where aldehydes might serve as intermediates in synthetic routes, points out Xumu Zhang, who founded catalyst producer Chiral Quest in 2000. He is also a chemistry professor at Rutgers, the State University of New Jersey, where he will head a new center for molecular catalysis. In 2006, Zhang and graduate student Yongjun Yan designed a phosphine-phosphite ligand for asymmetric hydroformylation called YanPhos (J. Am. Chem. Soc. 2006,128,7198). More recently, Zhang and coworkers have made diphosphite ligands with binaphthyl backbones (Tetrahedron Lett. 2007,48,4781). Recent results have shown that catalysts designed for hydrogénation work well in hydroformylation and vice versa, as well as in other transformations. Besides transition-metal-based asymmetric catalysis, industrial researchers employ a variety of synthetic strategies, including reactions with chiral directing groups or auxiliaries, organocatalysts, and biocatalysts (C&EN, Aug. 14,2006, page 15). The usefulness of the aminoindanol moiety as a chiral auxiliary was highlighted
about 15 years ago in Merck's synthesis of the HIV drug Crixivan, which at the time was one of the most complex molecules the company's chemists had synthesized (C&EN, June 20,2005, page 54). Among those researchers was Chris H. Senanayake, now Boehringer Ingelheim's vice president for chemical development. "In general, rapid development of en-
antiopure APIs is a highly challenging task, and chiral auxiliary-based approaches are still a frequently employed strategy," Senanayake says. Notable advantages include the ready availability of some powerful chiral auxiliaries as well as the proven generality with respect to substrates. In addition, these approaches are often easy to scale up in a timely manner.
Enzymatic Synthesis
Just Got Simpler
BioCatalytics
Broadest Collection Available Easy to Use: Just Add Water Animal Free Extensive Technical Support Customized Screening Metabolite Synthesis Many Additional Services
BioCatalytics, I n c . · 129 Ν Hill Ave, Suite 1 0 3 · Pasadena, CA 9 1 1 0 6 · USA BioCatalytics Europe GmbH · P a r k r i n g 18 · A - 8 0 7 4 Grambach · Austria w w w . b i o c a t a l y t i c s . c o m ·
[email protected] WWW.CEN-0NLINE.ORG
\Π
AUGUST 6, 2007
CIVER STORY
Boehringer Ingelheim's process chemists have used different auxiliary-based routes to make intermediates containing trifluoromethyl-substituted quaternary stereogenic centers. "The structural motif of the tertiary alcohol with a CF3 group attached to the carbon center is very difficult to install, and new methodologies needed to be developed," says Boehringer Ingelheim senior principal scientist Jinhua Jeff Song. In one case, the process involved generating a]9-tolyl methyl sulfoxide auxiliary in situ and then reacting it with a trifluoromethyl ketone to form the quaternary center in a one-pot operation (Org. Process Res. Dev. 2007,11,605). Meanwhile, Song and coworkers discovered a novel direct asymmetric trifluoromethylation of a keto ester using a trans-2-phenylcyclohexanol auxiliary (J. Org. Chem. 2007,72,292) that provided the CF3-substituted product with much higher selectivity. "But the most practical and cost-efficient approach used an asymmetric acetate aldol reaction directed by an aminoindanol-derived chiral auxiliary," Song explains. After preparing chiral acetate with the
in satisfactory selectivity, would be more aminoindanol in a one-pot process, they desirable," GSK research investigator Snipformed a lithium enolate and reacted it ing Xie says. That's because the auxiliary with a trifluoromethyl ketone to obtain the was required in stoichiometric quantialdol product. Then, after crystallizing the ties and had to be attached and removed. major diastereomer, they cleaved off the "These are clearly disadvantages, but fortuauxiliary by transesterification and recovered it (Org. Process Res. Dev. 2007, n> 534·)· nately the auxiliary was not expensive," Xie Likewise, GlaxoSmithKline researchers published three C O N V E R T I N G A L K E N E S Hydroformylation generations of syntheses for can make branched or linear aldehydes. making a tetrahydrocarbazole compound as a potential treatment for human papillomavirus infections, considered the most common sexually transmitted disease (Org. Process Res. Dev. 2007,11,539). says. Better yet, the reactions worked well and were scaled up to provide multikiloProgressing from an initial racemic syngrams of the compound at over 99.5% ee. thesis using chromatography or salt resoluGSK scientists also reported an optition, their next best route was a modestly mized asymmetric phase-transfer catasuccessful enantioselective reductive animalyzed (PTC) alkylation to make a nonnatution via chiral transfer hydrogénation with ral amino acid intermediate for a drug in Noyori-type ruthenium catalysts. The most development (Org. Process Res. Dev. 2007, efficient and selective synthesis was a diaste11,624). PTC reaction conditions typically reoselective reductive amination directed by are mild and use environmentally benign a chiral phenylethylamine auxiliary. reagents and solvents. Their process used "Enantioselective synthesis, if achieved
no acids amino acids b u i l d i n g blocks I unusual amino
acids .COOH
New Combinatorial Chemistry Catalog Available Now
• Prefer an experienced while nimble chemistry partner ... • Have a tight budget but a demanding deadline ... • Desire flexibility due to constantly changing priority ... Give us a call or drop an email
CHEMALONG Ph: 630.257.9683 Fax: 630.257.9684 Email:
[email protected] 800452-5530 Fax 408-452-5059
[email protected] www.anaspec.com
WWW.CEN-0NLINE.ORG
\Q
AUGUST 6, 2007
a cinchona alkaloid-derived chiral catalyst and avoided stoichiometric amounts of chiral auxiliaries and azide chemistry used in an earlier route. They believe it is one of very few published examples of asymmetric PTC using secondary alkyl halides. Research adviser Nicholas A. Magnus and coworkers at Lilly recently developed what they believe is the largest-scale demonstration of an enantioselective aryl transfer reaction. The goal was to produce a chiral diarylmethanol intermediate that could be converted to an acetate and subsequently used to make kilograms of compounds for development as mGlu2 receptor potentiators for treating migraine headaches (Org. Process Res. Dev. 2007, n> 560). "We considered all the typical known methods for converting an appropriate ketone into a chiral secondary alcohol, including asymmetric reduction by a catalyst or enzyme or by hydride reduction," Magnus explains. "But an early experiment using aryl transfer chemistry resulted in very high conversions and very good enantioselectivity, and given the timeline we were up against, we went with that." The synthesis starts with a postulated arylalkylzinc species, which is prepared by exposing a boroxine to diethylzinc. Reacting this with 3-cyanobenzaldehyde in the presence of an aminoalcohol organocatalyst yielded the desired diarylmethanol in greater than 94% ee. Reaction monitoring and analysis to understand optimal stoichiometrics and reaction end points helped control the process efficiently. In these reactions, a polymer additive often improves selectivity. Removing it meant the catalyst loading had to be increased slightly to maintain selectivity, but it allowed for an easier and cleaner workup and catalyst recycling. Ultimately, Magnus believes the most cost-effective, long-term solution would be an asymmetric reduction of a ketone by catalytic hydrogénation or an enzymatic process to give a chiral alcohol. A GOAL of early-phase process development is to rapidly identify a stable advanced intermediate around which one can set preliminary purity specifications, Magnus explains. The technology for preparing this intermediate is either developed internally or by a third-party provider, which ultimately prepares the material in bulk. This strategy enables more time for the internal process scientists to focus on developing the late-stage synthetic steps
with C&EN, is the need for determining an "E factor" for a process. "A health, safety, and environmental assessment is a critical criterion for acceptability in our process development," Magnus says. "It's got to be dealt with, and it's not taken lightly. If problems are insurmountable, or there is danger to the environment, a synthesis will be replaced." •
to ensure control of impurities in the final product. In a company's own plants or at an outside provider, an advanced intermediate will undergo its final transformations under strict regulatory conditions to become a product. Another aspect of process development, mentioned by almost all pharmaceutical company process chemists who spoke
cGMP Synthesis and
Bulk Intermediates Bulk Intermediates
cGMP Synthesis
Production in China
cGMP Kgs Scale
Medicinal Route
Polymorph Screening
Salt Selection New Drug Candidate
Best Salt Form for Optimal Properties
FTE Research
New Drug Candidates
Final Form for Clinical
Analytical R & D • Analytical Method dev and validation • Analytical Reference std • cGMP/GLP Lot Release • Trace Analyses • DVS.XRPD, DSC, TGA, Hot stage
FTE research in both process and medicinal chemistry in the U.S. or China
China
Kgs to Multi-Tons
U.S.
Please Call for Any R Group(s) You Want
PK-Catalyst Kg to commençai scale
Suzuki Reaction at Large Scale Made EASY! PHARMA TECH
Wilmington PharmaTech
Phone: 3 0 2 - 7 3 7 - 9 9 1 6 Fax: 3 0 2 - 2 6 1 - 7 0 0 0 Email:
[email protected] WWW.CEN-0NLINE.ORG
TO
AUGUST 6. 2007
