Chiral Quest Technology for Asymmetric Hydrogenation Applications and Gaps Dr Ian C. Lennon Senior Vice President, Global Business Development Chiral Quest Corp., Cambridge, UK ilennon@chiralquest.com
Expertise in Asymmetric Hydrogenation Hydrogenation reactors with high pressure capability (100 L to 1000 L) One 1000 L Hastelloy hydrogenation reactor, rated to 100 atm. Two 1000 L, two 500 L and one 100 L stainless steel hydrogenation reactors (100 atm.) One 1000 L and one 100 L glass lined hydrogenation reactor (10 atm.) Our own proprietary catalysts Vessels transferred from Suzhou to Long Life site, near Nanchang
Catalytic Asymmetric Hydrogenation Avoids wasteful production of 50% of the wrong isomer Over 70% of commercial asymmetric catalytic processes involve asymmetric hydrogenation Nobel Prize in Chemistry 2001 Asymmetric hydrogenation can be applied to make over 50% of all chiral moieties in pharma products
Application of Asymmetric Hydrogenation to Drugs
Chiral Quest Chiral Catalysts Catalysts all available on a Kg scale >30 kg of DuanPhos made to support manufacturing f-binaphane ligand soon to be available from Strem
Chiral Catalyst Composition Focus on Metal Rhodium is only 15% of the weight of the pre-catalyst The chiral ligand is 56% of the pre-catalyst weight In the Noyori catalyst - RuCl 2 [(S)-Xyl-BINAP][(S)-DAIPEN] Ruthenium is only 9.1% if the precatalyst by weight Commercially the most important factor for any catalyst is cost contribution
Manufacture of a-amino Acids Many a-amino acids are manufactured on a Kg to Metric Tonne scale
Methods to Make Hydrogenation Substrates J. Plochl. Chem. Ber. 1884, 17, 1616; E. Erlenmeyer, Chem. Ber. 1892, 25, 3445 R. W. Ratcliffe et al. Tetrahedron Lett. 1973, 4645 G. R. Beck et al. Synthesis. 1992, 741 J. G. DeVries et al. J. Org. Chem. 2006, 71, 2026
Manufacture of (S)-N-Boc-3,4-Difluorophenylalanine Vantia therapeutics made a request for 15 kg of (S)-N-Boc-3,4-Difluorophenylalanine The product was made, shipped and received by the customer in under 10 weeks from receipt of a purchase order Conditions for the Rh-DuanPhos hydrogenation are mild and scaleable. Chiral Quest is very cost competitive for a-amino acids on all scales
New Route to N-Boc-(S)-2,6-Dimethyltyrosine The Erlenmeyer route does not work for the sterically hindered aldehyde We have produced the Horner-Emmons reagent on a 5 MT scale This reagent is now routinely used for a-amino acid manufacture
4-Fluoro-D-phenylalanine Benzyl ester Ts Salt Chiral Quest has manufactured 5 and 50 kg lots of this product for CML Europe High enantiomeric excess (99.9%) and purity (99.5%) was achieved. Exceptionally good catalyst loading and low cost contribution to product
Ramipril The API went generic in 2008, but still has significant sales Ramipril sales in 2011 was $1.43 Billion and 45 MT of API was consumed Original route to intermediate is 10 steps with a late stage resolution
Chiral Quest s New Process for Ramipril Intermediate Vilsmeier-Haack reaction used to make the key aldehyde Erlenmeyer reaction with benzoylglycine provides the hydrogenation substrate 11 g of catalyst produces 400 kg of product, S/C = 80,000 (36,235/1 wt / wt )
Chiral Quest s New Process for Ramipril Intermediate Our route is 8 steps with a highly efficient asymmetric hydrogenation. This is a more environmentally friendly route to the Ramipril Intermediate >30 MT of the Ramipril intermediate has been made by this route. Patent application:- WO 2011/133651 A1. US 8,558,023, granted 15 th October 2013
The Importance of b-amino Acids for the Pharma Industry
Pfizer Application using Rh-Binapine Rh-Binapine used for the propyl and butyl analogues by Pfizer Later replaced by the Pfizer Rh-(R)-mTCFP system, which was more active, with lower selectivity Binapine ligands and catalysts have been made on a 10 kg scale. Javier Magano et al, Tetrahedron Letters, 2009, 50, 6329-6331
100 Kg Asymmetric Hydrogenation Scale-up Highly efficient asymmetric hydrogenation process, S/C = 4,000 1 kg of catalyst can produce >1,000 kg of product Chiral Quest has supplied this product on a multi-100 kg scale and can manufacture on a metric ton scale We can produce other analogues readily
Enantioselective Hydrogenation b-enamine Esters Xumu Zhang et al.: J. Am. Chem. Soc. 2010, 132, 12844-12846
(S)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline for Solifenacin Solifenacin was launched in 2004 for the treatment of Overactive Bladder The chiral amine can be manufactured using a classical resolution. Chiral Quest is developing an asymmetric hydrogenation process using an Iridium catalyst We need S/C = 30,000/1 to compete with the classical resolution! X. Zhang et al. Angew. Chem. Int. Ed. 2011, 50, 10,679-10,681
Large Scale Manufacture of Chiral Amines Chiral amines have been manufactured by Chiral Quest using Asymmetric Hydrogenation on a 50 kg to >1,000 kg scale
Intermediate for Rivastigmine Chiral Quest has developed a new route to a Rivastigmine Intermediate It is two simple steps from the API We have made >20 kg of this intermediate and have made 10 kg of 3-[(1S)-1- (Dimethylaminoethyl)]phenol. A sample has been converted into the API
Synthesis of a Dorzolamide Intermediate Asymmetric hydrogenation of methyl acetoacetate requires a Hastelloy reactor Chiral Quest has a 1,000 L Hastelloy hydrogenation vessel >3MT of this intermediate has been manufactured
Intermediate for Aprepitant In excess of 4 MT of the chiral alcohol for Aprepitant has been manufactured Excellent catalyst loading, concentration and ee competes very well with ADH!
Chiral Quest s Approach to the Key Intermediate of Duloxetine >10,000 kg of MMAA has been manufactured, >99% ee, >99% purity Process transferred to Jiang Xi Long Life and is in routine production. Aiming for 50 MT production per year Chiral Quest has filed a US DMF for the MMAA process Ref. Number 26862
Commercial Manufacture of MMAA 2200 kg of MAK.HCl has been made at CQS 16 x 1000 L asymmetric hydrogenation reactions have been successfully completed at a S/C = 9,000 (2730/1 wt / wt ) >1300 kg of MMAA has been manufactured, >99% ee, >99% purity Typical concentration for asymmetric hydrogenation is 104 kg in a 1000 L vessel Thus demonstrating that the asymmetric hydrogenation process is reproducible and robust over multiple runs. Catalyst loading being lowered during commercial production.
Chiral Quest s Route to Sitagliptin Intermediate Highly efficient asymmetric hydrogenation process, S/C = 5,000 (2,360/1 wt / wt ) Three manufacturing campaigns completed >6,000 kg made. Granted patent, US 8,278,486 B2,Oct 2 nd, 2012. Pending in Europe, China and India Chiral Quest has filed a US DMF for the Sitagliptin process Ref. Number 27115
Gaps in Asymmetric Hydrogenation Chiral Amines are still challenging via Enamide is 4 steps from ketone Oximes and Enamines cannot be hydrogenated in an asymmetric fashion Imines are challenging for catalyst loading, hence economics can get good ee. Asymmetric reductive amination suffers from poor catalyst loading and hence economics. Steric Hindrance leads to higher catalyst loading, hence higher cost contribution. Some b-amino acids are still made via classical resolution due to poor catalyst loading a-amino acids, chiral alcohols, itaconates and some amines are easily made 2-Substitution on enamides, methyl ethyl ketone, some cyclic ketones are challenging Pfaltz type isolated double bonds are challenging poor catalyst loading, high pressure but these are chiral grease!
A Recognized Leader in Chiral and Process Chemistry Ian Lennon ilennon@chiralquest.com April 2014