Hello blucken,
Here is what I have been able to find.
Phosphines were key to the work done by two of the three winners of
the 2001 Nobel Prize in Chemistry, and pharmaceuticals are one of the
key applications of this work.
http://www.nobel.se/chemistry/laureates/2001/public.html (Nobel web site)
A molecule is said to be chiral when its structure can assume two
forms called enantiomers, one being a mirror image of the other. This
is the case with proteins, carbohydrates and nucleic acids, but only
one of these enantiomers occurs in nature. Therefore, enzymes and cell
receptors are also chiral. Most drugs are also made of chiral
molecules. Drugs work by binding to cellular receptors, enzymes, etc.
and often only one of the drug enantiomers will have the desired
activity, while the other one could be inactive or even toxic.
Therefore, drug companies are keen to be able to produce more of the
desired enantiomer and less or none of the unwanted one.
While working at Monsanto, William Knowles discovered that he could
use a chiral phosphine to produce a catalyst that would result in more
of one enantiomer of a compound being formed in a hydrogenation
reaction. This discovery was applied to the synthesis of L-DOPA, which
is used in the treatment of parkinsonism. This was the first ever
catalytic asymmetric synthesis.
The catalyst used by Monsanto in the industrial production of L-DOPA
is the diphosphine ligand DiPAMP.
The development of improved asymmetric hydrogenation catalysts is very
important both for economic reasons and also, by reducing waste
products, for environmental reasons.
The second Nobel winner, Ryoji Noyori, synthesized the the diphosphine
ligand BINAP, which, when complexed with ruthenium, is used as a
catalyst in the production of (R)-1,2-propandiol, which is needed for
the industrial synthesis of the antibiotic, levofloxacin.
In September 2002, Rhodia?s Phosphorus and Performance Derivatives
(PPD) enterprise ?acquired exclusive rights to the phosphine coupling
technology owned by Great Lakes Chemical Corporation. Such technology
will enable Rhodia to develop the processes and manufacture various
Phosphine ligands, including Nobel Prize winning BINAP.
? This technology was originally discovered and patented by Monsanto
in U.S. Patent 5,874,628 and subsequently licensed by GLCC when they
acquired NSC Technologies.?
http://www.rhodia-ppd.com/news.asp?show=1242 (Rhodia web site)
In June 2001, Rhodia PPD entered into partnership with Nippon Chemical
Industrial Co. Limited and Hokko Chemical Industry Co. Limited with
the specific aim of extending its phosphine manufacture. At that time,
Rhodia estimated ?the size of the phosphine derivatives market is 280m
Euros (excluding phosphonium salts), expanding by 10 to 15% every
year. This growth is attributed to increased demand from the fine
chemicals, pharmaceutical and petrochemicals markets. Necessary
components in these markets are catalysts, of which phosphines are an
essential part. Within the pharmaceutical market the rapid growth of
chiral chemistry requires new and better chiral phosphines? Earlier
that year, Rhodia first started manufacturing chiral phosphine
ligands, having obtained an exclusive contract to produce the DuPHOS
product range for Chirotech.
?Rhodia Joins Forces with Nippon and Hokko Chemical? Rhodia press
release 12 June 2001
http://www.rhodia-ppd.com/news.asp?show=381
However, following the takeover of Chirotech by Dow in the same year,
use of DuPHOS technology for pharmaceutical applications was brought
back inhouse.:
?Pharmaceutical Services from Dow Secures Exclusive Rights to DuPHOS?
Asymmetric Hydrogenation Technology for Pharmaceutical Applications
Midland, MI - December 04, 2002
http://www.dow.com/dow_news/prodbus/2002/20021204a.htm (Dow Chemical
Company web site)
?The Pharmaceutical Services business unit of The Dow Chemical Company
has secured exclusive rights to DuPontTM DuPHOSTM asymmetric
hydrogenation technology, licensed from DuPont for pharmaceutical
applications.?
?.
?Asymmetric chemocatalysis is a rapidly developing area of innovation,
as researchers look for new ligands and catalysts that are more
active, more selective, and more broadly applicable in the commercial
arena," explained Nick Hyde, Business Director for Pharmaceutical
Services. "We use asymmetric chemocatalysis extensively, in
applications ranging from the manufacture of single-enantiomer chiral
intermediates from prochiral precursors, to the building of more
complex structures such as chiral scaffolds for pharmaceutical
discovery.?
?Hyde added. ?We now have an enviable number of choices available in
our catalyst toolbox. In addition to well-established DuPHOSTM
technology, we offer a broad range of complementary catalyst systems
for asymmetric hydrogenation processes. In particular, under
Chirotech's license from the Japan Science and Technology Corporation,
we have access to the powerful and versatile Noyori technology for
ketone hydrogenation.?
Pharmaceutical Services follows a flexible approach to satisfying
customer needs for catalyst technology. Pharmaceutical Services will
manufacture products (building blocks, advanced intermediates, and
APIs) for customers where chemocatalysis is used as a key step.
Customers can also license catalysts from Pharmaceutical Services for
use in their own manufacturing facilities, and they can utilize Dow's
screening and development service to identify the best choice of
catalyst for their individual situation.?
One pharmaceutical use of DuPHOS was presented as an example at the
conference ?Chiral USA 2000?, a report of which is available on the
web site of Albany Molecular Research Inc.
http://www.albmolecular.com/features/tekreps/vol04/no40/
"Modularity in Asymmetric Catalysis: Advantages and Practical Applications"
by Mark J. Burk, (Chirotech Technology Ltd.
?Chirotech was contracted by Pfizer to identify an optimal catalyst
for hydrogenation of a key intermediate in the synthesis of
Candoxatril 8, a compound used to treat congestive heart failure. The
key step in the synthesis was designed around asymmetric hydrogenation
of the acid 6 followed by a series of transformations to generate the
final product 8. After screening the available DuPHOS and BPE ligands
for selectivity in this critical transformation it was found that the
(S,S)-methyl DuPHOS Rhodium complex provided the necessary material in
99%ee. The final process employed the optimal Rhodium complex and was
found to provide acid 7 in a 97% isolated crude yield with substrate
to catalyst ratio of 3500/1 and was demonstrated on a 12 kg scale in
the Pfizer pilot plant.?
?Phosphines are expensive and are often difficult and very time
consuming to make in reasonable quantities ? but recently Jianliang
Xiao and his team discovered how to make phosphines faster and more
economically, using novel parallel catalytic processes.
These processes are generic: they can be used to make chiral and
non-chiral phosphines, phosphines with particular steric or electronic
properties, and hydrophilic or hydrophobic phosphines. "We?ve also
used them to make phosphines of novel utility", says Jianliang Xiao ?
"for instance, those that are water-soluble, electron-rich or poor."
Liverpool University has licensed this technology to Johnson Matthey plc
?Johnson Matthey and its Synetix business will use the technology to
enhance bulky chemical processes, fine chemical synthesis and
asymmetric catalysis ? creating intermediaries for pharmaceutical
applications?
Article on the Leverhulme Centre for Innovative Catalysis, University of Liverpool.
http://www.liv.ac.uk/researchintelligence/html/current/07.html
Synetix was previously the catalyst division of ICI.
Synetix has a number of phosphines for asymmetric hydrogenation, which
are pictured on its web site
http://www.synetix.com/chiraltechnologies/technologies-hydrogenation.htm
as are some new bulky phosphine ligands
http://www.synetix.com/chiraltechnologies/technologies-heck.htm
http://www.synetix.com/chiraltechnologies/technologies-suzuki.htm
and a BINAP-based catalyst for asymmetric hydroamination
http://www.synetix.com/chiraltechnologies/technologies-enantioselective.htm
Strem Chemicals Inc.
http://www.strem.com/code/index.ghc
Links to pdf files with information about phosphone products supplied
by the company for research purposes, for example:
?Tri-t-butyl and tri-n-butylphosphonium tetrafluoroborates, developed
by Professor Gregory Fu?s group, are remarkably air- and
moisture-stable compounds compared to the malodorous and pyrophoric
parent phosphines. Furthermore, Professor Fu has demonstrated that the
phosphonium salts can be used as direct replacements for the neat
phosphine in a variety of stoichiometric and catalytic processes. The
free phosphine can be easily generated in situ by adding a Brønsted
base. Based on this simple, yet powerful strategy, Strem is pleased to
provide researchers with an assortment of trialkylphosphonium
tetrafluoroborates.?
Chiral Quest
http://www.chiralquest.com/
?Chiral Quest is a life sciences chemistry company dedicated to
providing innovative asymmetric products and services to the
pharmaceutical/biotechnology and fine chemical industries. Its array
of catalysis products and technology - based on proprietary expertise
- is designed to facilitate the development of chiral molecules, which
comprise over one-third of all drugs currently on the market. Chiral
Quest aims to become a leading, high value technology provider and
partner in the chiral therapeutics industry by offering proprietary
catalysts, novel building blocks for discovery, and collaborative
synthetic solutions. Listed in the US public market (CQST), Chiral
Quest is the only quoted firm worldwide dedicated exclusively to this
significant area.?
?Chiral Quest is the exclusive worldwide licensee of new chiral
technologies developed by Professor Xumu Zhang at Penn State
University.?
http://www.chiralquest.com/about/index.html
?Chiral Quest Announces Chiral Drug Manufacture R&D Agreement with Clariant
Ltd.
State College, PA-October 2, 2002? Chiral Quest announced today an agreement with
BU Pharma, a Division of Clariant Fine Chemicals, involving the development of a
manufacturing process of a significant chiral antibiotic active
pharmaceutical ingredient?
http://www.chiralquest.com/documents/Clariant.pdf
?Chiral Quest Adds U.S. Patent for Cn-TunePhos to Patent Portfolio
State College, PA - February 27, 2003 ? Chiral Quest, Inc. (OTC Bulletin Board:
CQST) today announced that the U.S. Patent and Trademark Office has issued a
patent (No. 6,521,769) covering the compositions of matter and use for a series of
transition metal catalysts derived from chiral biaryl phosphines with a tunable
dihedral angle to The Penn State Research Foundation, a non-profit corporation.
?
?The tunable nature of the TunePhos family of ligands gives Chiral
Quest the ability
to selectively modify reactions to get desired results,? remarked Professor Xumu
Zhang, Chief Technology Officer of Chiral Quest. ?Since we can systematically alter
the chiral environment of the chemical reactions, this ligand gives us
more flexibility
in practical applications than any other ligand.??
http://www.chiralquest.com/documents/PatentTunephos.pdf
?Chiral Quest Receives U.S. Patent for Ferrocene Amide Phosphine
State College, PA ? April 3, 2003 ? Chiral Quest, Inc. (OTC Bulletin Board: CQST)
today announced that the U.S. Patent and Trademark Office has issued a patent
(No. 6,534,657) covering the compositions of matter and use for a series of chiral
phosphine ligands and catalysts with ferrocene backbones to The Penn State
Research Foundation, a non-profit corporation.
?
"This patent discloses some effective methods for making carbon-carbon bonds,
which is potentially usefully to prepare an array of biologically
active drug-like chiral
molecules,? remarked Professor Xumu Zhang, CTO of Chiral Quest.?
http://www.chiralquest.com/documents/PatentFAP.pdf
?tate College, PA ? July 10, 2003 ? Chiral Quest, Inc. (OTC Bulletin Board: CQST)
today announced that the U.S. Patent and Trademark Office has issued a patent
(No. 6,576,772) covering composition of matter for chiral bisphosphine ligands
derived from D-mannitol to The Penn State Research Foundation, a non-profit
corporation.
?
DIOP* ligand differs from well-known DIOP ligand in its conformational stability.
Methyl groups and other substituents in DIOP* are oriented in equatorial positions.
This conformational difference has produced a dramatic increase of
enantioselectivity for the hydrogenation of enamides.
?
?We are the only life sciences chiral chemistry company in the market with
proprietary ligands for chiral reactions representing each class of
important chiral
phosphines,? commented Alan Roth, Ph.D., President and Chief Executive Officer of
Chiral Quest.?
http://www.chiralquest.com/documents/PatentDIOPFINAL.pdf
Cytec Canada Inc (speciality chemicals division of Cytec Industries Inc
?Cytec's newest growth markets for phosphines and its derivatives are
the chemical and pharmaceutical industries, where organophosphines are
increasingly used as catalyst ligands for a variety of products or
chemical processing operations. Phosphonium salts are gaining
acceptance as phase transfer catalysts and biocides, and as
replacements for ammonium salts in these applications.?
http://www.cytec.com/business/SpecialtyChemicals/phosphinechemicals.shtm
?While phosphine ligands and their complexes have been studied for
many years, a rebirth of activity is underway as workers seek to find
improvements in ligand design not only for homogeneous catalysis and
asymmetric synthesis but for site-specific drug delivery. The
rapidity with which new syntheses of unsymmetrical ditertiary
phosphines are announced and the regularity of reports of new chiral
phosphines, including combinatorial synthetic procedures, affirm the
current intense interest in phosphine science. Only a few years ago
few would have imagined complexes bearing phosphine ligands as
candidates for pharmaceutical application, but now water-soluble
phosphines with potential for stabilizing radiopharmaceutical
complexes in vivo with links to target-directing biomolecules are
under intense study.?
Research interests page of Prof. Richard L. Keiter, Eastern Illinois University
http://www.eiu.edu/~eiuchem/faculty/RKeiter.htm
An article in Chemical Market Reporter, December 9, 2002 looks at the
use of chiral technologies in the pharmaceutical industry.
The article is at
http://www.candmconsult.com/120902Challener_RO.pdf
Here is a summary of the relevant points made in the article:
Single-enantiomer compounds are the main ingredients in the
best-selling drugs. Sales of chiral drugs in 2001 were $147 billion,
just over a third of all drug sales. Synthetic chiral chemistry was
used to make compounds accounting for $60 billion of this total, and
the value of the chiral intermediates was $7.3 billion. Chiral
products make up 82% of all antibiotic, antifungal and haematology
drugs, 71% of hormonal drugs, 60% of cardiovascular drugs. Chiral
technologies are considered to be the fastest growing sector of the
speciality chemicals market.
However, some consider that the market for chiral technologies is
becoming overcrowded. Pharmaceutical companies form the major part of
that market, and their demands fluctuate. Nick Hyde of Dow is quoted
as saying that manufacturing companies in asymmetric catalysis need to
integrate this with other capabilities in order to offer complete
solutions, and Peter Michels from Albany Molecular Research Inc
stresses the need for flexibility. Jean-Claude Caille of PPG-Sipsy
thinks that new catalysts must be developed with the same specificity
and efficiency as enzymes. He also says that while many chiral
diphosphine ligands have been discovered, there is a need for new
concepts in order to develop new generations of catalysts.
Immobilisation of homogenous chiral catalysts is seen as a crucial
accompanying technology.
The number of alliances and licensing arrangements relating to chiral
technology is increasing, because no single company is able to invent
all the technology it needs.
Examples of such arrangements include: Rhodia Chirex with MIT, Harvard
and Scripps; PPG-Sipsy is licensing a diphosphine ligand from Roche;
Bayer has several collaborations with academia and smaller companies;
Degussa developed and patented its new MalPhos catalyst together with
IFOK (Institute for Organic Catalysis Research) in Rostock.
A report issued in October 2003 that looks at the investment potential
in Chiral Quest quotes analysts Frost and Sullivan as forecasting that
global revenues from chiral technology will increase from $6.6 billion
in 2000 to $16 billion in 2007, a compound annual growth of 13%. [The
pharmaceutical industry is the main buyer in this market, and
phosphines form a key element of one part of the technology.]
The same analysts estimate that chiral pool technology and resolution
(ie separation of one enantiomer from another) currently account for
55% of revenue, while chemical asymmetric methods account for 35% and
biological asymmetric methods for 15%. However, they forecast that the
latter two groups of technologies will account for an increasing
proportion revenue while revenue from traditional technologies will
decrease in the period 2002-2009.
This report lists the following companies as being in the same market
as Chiral Quest with respect to asymmetric chiral technology: Avecia
(UK), BASF (Germany), Bayer (Germany), Codexis (USA), Degussa
(Germany), Lonza Group (Switzerland), Mercian Corp (Japan), Takasago
Corp (Japan), Precision Biochemicals Inc, Solvias AG (Switzerland),
Ventria Bioscience (USA), and Rhodia, Dow, Synetix which have already
been listed above. The appendix to the report contains more
information about these competing companies. It also contains masses
of other highly-detailed background information, and is likely to be
worth reading in its entirety.
It can be accessed at:
http:// www.cohenresearch.com/reports/chiral2_10_19_03.pdf
(Web site of Cohen Independent Research Group)
The CMR article cited above does however state that biocatalysis has
started to become a viable alternative to chemical catalysis, and and
a press release for the 2003 ACHEM Congress on chemical engineering
states:
?So far, the catalysts used for chiral reactions are mostly made of
platinum-group metals, combined with phosphine ligands. However, a
fast-growing market is developing for enzymes ? these are naturally
occurring catalysts that are highly selective in their function. The
market for biocatalysts is growing at 9.5%/year. and is expected to
reach $33 million by 2006, according to market research company The
Freedonia Group, Inc.?
http://aurum2.dechema.de/achema2003/new/presse/tb13e.htm
I hope that this answer has given you at least some of the information
you are seeking, but please do not hesitate to request further
clarification if required.
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