License of JST Catalyst Technology Expands Dowpharma’s Chiral Commercial Production Capabilities

Midland, MI - April 15, 2003

Dowpharma^SM, a business unit of The Dow Chemical Company, announced the license extension of the pressure hydrogenation and the transfer hydrogenation catalysts introduced by Nobel Laureate Professor Ryoji Noyori and Professor Takao Ikariya via the Japanese Science and Technology Corporation (JST). These hydrogenation technologies are rapidly establishing themselves as the superior methods for cost-effective commercial-scale manufacture of single enantiomer aryl and allyl alcohols. This is due to the excellent activity and selectivity the catalyst produces, process conditions that are readily scaled-up (only moderate pressure and temperatures are required), minimal waste streams and straightforward reaction work-up.

"This license extension allows Dowpharma to support our customers’ projects by practicing this technology at full commercial scale," said Nick Hyde, business director, Dowpharma. "The hydrogenation catalysts have a wide range of applicability and enhance the speed of development of chiral compounds. The technology has demonstrated superior results as we’ve scaled up from lab to pilot plant to commercial production."

Professor Ikariya added, "It is always good when breakthrough chemistry that has been developed in an academic environment starts to add value in the commercial environment. It is made more special in this case when these technologies are used to produce a new generation of complex medicines that will improve the quality of lives of thousands of people around the world."

Dowpharma’s agent for Japan, CBC Corporation, played a pivotal role in securing the extension of this technology from Chirotech Technology Limited for Dowpharma’s pharmaceutical manufacturing facilities in Midland, Michigan. Chirotech is part of the Dowpharma business unit.

The introduction of the pressure hydrogenation and the transfer hydrogenation catalysts is another example of Dowpharma’s continuing expansion of its chiral toolbox. Recent announcements have been made regarding asymmetric allylation and asymmetric aldol chemistries licensed from Stanford University, the exclusive rights to DuPhos^TM asymmetric hydrogenation technology, licensed from DuPont, as well as Dowpharma’s expansion of asymmetric hydroformylation. Dowpharma remains one of the leading chiral players in the pharmaceutical industry.

Enabling Production at a New Scale
Catalytic asymmetric hydrogenation of ketones is a key technology for the cost-effective commercial scale production of chiral alcohols of high enantiomeric purity, which are important intermediates in pharmaceutical and agrochemical syntheses.

With the license extension, Dowpharma can practice the Noyori technologies at full commercial scale. Dowpharma can now serve customers at any stage of their product lifecycle, from lab to kilo quantities to validation to commercial launch, at Dowpharma’s facilities in Cambridge and Mirfield in the United Kingdom and at its large-scale cGMP plants in Midland, Michigan.

Hyde noted Dowpharma’s commitment to chiral technology. "With our acquisition of Chirotech in 2001, Dowpharma became one of the world leaders in asymmetric chemocatalysis. Dowpharma continues to invest in chiral technologies and we differentiate ourselves with a range of chiral technologies that are industrially ready. These technologies have established supply chains for catalyst manufacture and are available at the full spectrum of scale that our customers may need."

For pressure hydrogenation, the [(diphosphine)RuCl₂ (1,2-diamine)] complexes are excellent precatalysts for homogeneous hydrogenation of prochiral ketones, including aromatic-, heteroaromatic- and amino-ketones, as well as cyclic and acyclic α,β-unsaturated ketones giving consistently high enantiomeric excess (often greater than 99% ee). This can be achieved with very good utilization of catalyst, with some processes operating at substrate-to-catalyst ratios of 100,000 or higher.

"Dowpharma has the unique advantage of being able to access a range of novel diphosphines for these applications, including PhanePhos, HexaPHEMP and DuPhos^TM ," added Hyde. "A wide range of these modular catalysts are available to screen against substrates. When a catalyst has been identified, a process can be taken from the laboratory and scaled-up to multi-100 kilograms in a matter of months."

Complementary to the pressure hydrogenation is the transfer hydrogenation technology, using simple ruthenium systems and formic acid or propan-2-ol as the hydrogen source. Products can be manufactured in standard vessels, as hydrogen gas is not required. Ketones with acid- or base-sensitive substituents can be reduced in high yield, and the technology is also effective for the asymmetric hydrogenation of imines.

About Dowpharma
As part of Dow’s Custom & Fine Chemicals global business unit, Dowpharma serves the pharmaceutical and biopharmaceutical industries with innovative technology, products and services for clients in drug discovery, development, manufacturing and delivery. Dowpharma combines the resources and capabilities of several entities to create a single, market focused organization with broad service and support capabilities for large and emerging pharmaceutical companies.

Dowpharma services include process development, route selection, methods development and associated analytical services and manufacturing and scale-up from the bench through clinical trials and to commercial launch. Dowpharma currently manufactures small molecule Active Pharmaceutical Ingredients (APIs) and intermediates, oligonucleotides, peptides, cGMP polymers and proteins from microbial fermentation.

Dowpharma has an excellent 20-plus year history of cGMP regulatory compliance in the organic synthesis of APIs and pharmaceutical intermediates with the ability to provide client support in filing and validation strategies. The business also manufactures a long list of scaffolds and fine chemicals of interest to the drug development community. This business combines personnel and assets from Dow’s Contract Manufacturing Services business with those from Chirotech Technology Limited, Mitchell Cotts Chemicals, Hampshire Chemical Corp., and Dow Biopharmaceutical Contract Manufacturing Services. Dowpharma operates research, process development and manufacturing facilities in North America and Europe.

For more information on Dowpharma: www.dowpharma.com

About Dow
Dow is a leading science and technology company that provides innovative chemical, plastic and agricultural products and services to many essential consumer markets. With annual sales of $28 billion, Dow serves customers in more than 170 countries and a wide range of markets that are vital to human progress, including food, transportation, health and medicine, personal and home care, and building and construction, among others. Committed to the principles of Sustainable Development, Dow and its approximately 50,000 employees seek to balance economic, environmental and social responsibilities.

For Editorial Information:

Kathleen Wilson
The Dow Chemical Company
989-636-2760


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These hydrogenation technologies are rapidly establishing themselves as the superior methods for cost-effective commercial-scale manufacture of single enantiomer aryl and allyl alcohols. This is due to the excellent activity and selectivity the catalyst produces, process conditions that are readily scaled-up (only moderate pressure and temperatures are required), minimal waste streams and straightforward reaction work-up. "This license extension allows Dowpharma to support our customers’ projects by practicing this technology at full commercial scale," said Nick Hyde, business director, Dowpharma. "The hydrogenation catalysts have a wide range of applicability and enhance the speed of development of chiral compounds. The technology has demonstrated superior results as we’ve scaled up from lab to pilot plant to commercial production." Professor Ikariya added, "It is always good when breakthrough chemistry that has been developed in an academic environment starts to add value in the commercial environment. It is made more special in this case when these technologies are used to produce a new generation of complex medicines that will improve the quality of lives of thousands of people around the world." Dowpharma’s agent for Japan, CBC Corporation, played a pivotal role in securing the extension of this technology from Chirotech Technology Limited for Dowpharma’s pharmaceutical manufacturing facilities in Midland, Michigan. Chirotech is part of the Dowpharma business unit. The introduction of the pressure hydrogenation and the transfer hydrogenation catalysts is another example of Dowpharma’s continuing expansion of its chiral toolbox. Recent announcements have been made regarding asymmetric allylation and asymmetric aldol chemistries licensed from Stanford University, the exclusive rights to DuPhos^TM asymmetric hydrogenation technology, licensed from DuPont, as well as Dowpharma’s expansion of asymmetric hydroformylation. Dowpharma remains one of the leading chiral players in the pharmaceutical industry. Enabling Production at a New Scale Catalytic asymmetric hydrogenation of ketones is a key technology for the cost-effective commercial scale production of chiral alcohols of high enantiomeric purity, which are important intermediates in pharmaceutical and agrochemical syntheses. With the license extension, Dowpharma can practice the Noyori technologies at full commercial scale. Dowpharma can now serve customers at any stage of their product lifecycle, from lab to kilo quantities to validation to commercial launch, at Dowpharma’s facilities in Cambridge and Mirfield in the United Kingdom and at its large-scale cGMP plants in Midland, Michigan. Hyde noted Dowpharma’s commitment to chiral technology. "With our acquisition of Chirotech in 2001, Dowpharma became one of the world leaders in asymmetric chemocatalysis. Dowpharma continues to invest in chiral technologies and we differentiate ourselves with a range of chiral technologies that are industrially ready. These technologies have established supply chains for catalyst manufacture and are available at the full spectrum of scale that our customers may need." For pressure hydrogenation, the [(diphosphine)RuCl₂ (1,2-diamine)] complexes are excellent precatalysts for homogeneous hydrogenation of prochiral ketones, including aromatic-, heteroaromatic- and amino-ketones, as well as cyclic and acyclic α,β-unsaturated ketones giving consistently high enantiomeric excess (often greater than 99% ee). This can be achieved with very good utilization of catalyst, with some processes operating at substrate-to-catalyst ratios of 100,000 or higher. "Dowpharma has the unique advantage of being able to access a range of novel diphosphines for these applications, including PhanePhos, HexaPHEMP and DuPhos^TM ," added Hyde. "A wide range of these modular catalysts are available to screen against substrates. When a catalyst has been identified, a process can be taken from the laboratory and scaled-up to multi-100 kilograms in a matter of months." Complementary to the pressure hydrogenation is the transfer hydrogenation technology, using simple ruthenium systems and formic acid or propan-2-ol as the hydrogen source. Products can be manufactured in standard vessels, as hydrogen gas is not required. Ketones with acid- or base-sensitive substituents can be reduced in high yield, and the technology is also effective for the asymmetric hydrogenation of imines. About Dowpharma As part of Dow’s Custom & Fine Chemicals global business unit, Dowpharma serves the pharmaceutical and biopharmaceutical industries with innovative technology, products and services for clients in drug discovery, development, manufacturing and delivery. Dowpharma combines the resources and capabilities of several entities to create a single, market focused organization with broad service and support capabilities for large and emerging pharmaceutical companies. Dowpharma services include process development, route selection, methods development and associated analytical services and manufacturing and scale-up from the bench through clinical trials and to commercial launch. Dowpharma currently manufactures small molecule Active Pharmaceutical Ingredients (APIs) and intermediates, oligonucleotides, peptides, cGMP polymers and proteins from microbial fermentation. Dowpharma has an excellent 20-plus year history of cGMP regulatory compliance in the organic synthesis of APIs and pharmaceutical intermediates with the ability to provide client support in filing and validation strategies. The business also manufactures a long list of scaffolds and fine chemicals of interest to the drug development community. This business combines personnel and assets from Dow’s Contract Manufacturing Services business with those from Chirotech Technology Limited, Mitchell Cotts Chemicals, Hampshire Chemical Corp., and Dow Biopharmaceutical Contract Manufacturing Services. Dowpharma operates research, process development and manufacturing facilities in North America and Europe. For more information on Dowpharma: www.dowpharma.com About Dow Dow is a leading science and technology company that provides innovative chemical, plastic and agricultural products and services to many essential consumer markets. With annual sales of $28 billion, Dow serves customers in more than 170 countries and a wide range of markets that are vital to human progress, including food, transportation, health and medicine, personal and home care, and building and construction, among others. Committed to the principles of Sustainable Development, Dow and its approximately 50,000 employees seek to balance economic, environmental and social responsibilities. For Editorial Information: Kathleen Wilson The Dow Chemical Company 989-636-2760
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