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From Genomes to Biotransformation Scale Up” 05 November 2014 Presentdted at RSC/SCI Symposium “Challenges in Catalysis for Pharmaceuticals and Fine Chemicals” by Dr

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From Genomes to Biotransformation Scale Up” 05 November 2014 Presentdted at RSC/SCI Symposium “Challenges in Catalysis for Pharmaceuticals and Fine Chemicals” by Dr “From Genomes to Biotransformation Scale Up” 05 November 2014 presentdted a t RSC/SCI Symposium “Challenges in Catalysis for Pharmaceuticals and Fine Chemicals” by Dr. Stefan Mix . Dededcatedteaicated team of ch emi sts, m oecuaolecular boogstsabiologists an dad an aystsalysts . Extensive track record in use of enzymes to produce chiral intermediates / APIs / bulk chemicals . Enzyme kits: Hydrolase, CRED, TAm, Nitrilase, P450s….. Enzyme discovery and evolution . Scouting of biocatalytic synthesis routes . Enzyme screening and scale -up (internal and with partners) . Metabolite isolation, identification and synthesis “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Exploring manufacturing routes to chiral b uildi ng bloc ks an d APIs: Relevance of chiral drugs 1000 Classical Resolution 800 600 billion US$ All drugs 400 single enantiomer drugs 200 0 Chirality 1998 1999 2000 2010 Year Chemo / Organo Catalysis The trend for new chiral pharmaceutical reagents is Chiral Pool continuing. In 2000, 35% of intermediates were chiral and this number is expected to increase to 70% by 2010 Biocatalysis Woodley et al TRENDS in Biotechnology Vol.25 No.2, 2006 “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Technology Oxidise Esterify Epoxidise Reduce Reduction to -OH Form amine Hydrolyse to amide Hydrolyse to acid Oxidise Demethylate Hydroxylate Hydroxylate Dihydroxylate Hydrolyse to acid Form an amide Esterify carboxyl Hydrolyse amide From ketone “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Biocatalytic Approaches to Statin Side Chains OC(O)CH2OMe OC(O)CH2OMe OH O O O A EtO HO HO O OEt -Chymo- O OEt PLE O OEt trypsin 98.1% e.e. KCN Nitrilase O OH OH B Cl NC CN NC COOH >95 % e.e. O O O ADH OH O O OH OH O C Cl Cl R OR OC(CH3)3 OC(CH3)3 > 99.5% e.e. O O ADH OH O HHDHO O HHDH OH O D Cl Cl NC OEt (S) OEt (S) OEt (R) OEt Schürmann et al. (2010) in “Green > 99% e.e. Chemistry in the Pharmaceutical Industry” OH (Eds. P.Dunn, A.Wells, O O DERA OH OH O M.T.Williams), Wiley-VCH O E Cl + Cl Cl OH 2eq. 96.6% d.e. “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Enzyme Platforms Product Classes Aldolases Alcohols, Diols, Amino alcohols Proteases Peptides, Amines, Carboxyesters Extensive portfolio Lipases and Esterases Alcohols, Esters, Carboxylic acids of off-the-shelf Ammonia lyases Amino acids enzymes: Hydantoinases, Carbamoylases, Racemases Amino acids • Made in-house Amidases Amino acids, Amides • From partners Acylases Amino acids, N-Acetyl-Amino acids Hy droxyn itr ile lyases ChdiCyanohydrins On-going enzyme Omega-Transaminases Amines discovery programs: • In-house Carbonyl Reductases Alcohols • With industry AA Dehydrogenases Amino acids partners Nitrilases Carboxylic acids, Nitriles • With academic Nitrile hydratases Amides, Nitriles partners Monooxygenases (P450 , Baeyer-Villiger) Alcohols, Sulfoxides Epoxide hydrolases Epoxides, Diols Haloalcohol dehalogenases Epoxides, Diols “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Biocatalyst libraries off-the-shelf: Speed matters! mg-10g 100g-1Kg 1Kg-100Kg >100Kg “Off-the-shelf” biocatalysts Process Dev Speed COST “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Recombinant enzymes – how they are made: Homogenisation Freeze- or Spray- & Clarification drygying Cell pasteLiquid CFE Solid CFE • Whole cell biocatalysts are cheapest, but CFE often preferred. • Further protein purification is possible, but reduces fermentation yield and increases cost. • Scale up of fermentation, homogenisation and freeze/spray-drying needs PRD! “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Case Studies: Biotransformation route scouting and PRD at Almac, scale up at Almac / other CMO or client “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] What do these molecules have in common? They are important pharmaceutical intermediates. AikdiikihihiAsymmetric ketone reduction is key step in their synthesis. They have been made via bioreduction at Almac. “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Case study: (R)-3-Methoxydecanol Application of CRED technology enabled large scale manufacture of chiral building block for late phase API. Success Criteria: Quality, Quantity, Speed, Cost “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Case study: (R)-3-Methoxydecanol Why was a new approach needed? Noyori route too expensive, tedious impurity removal, MedChem route very inefficient , ee borderline – hard to scale, and could not Could not meet late phase deliver >99% ee requirements “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Case study: (R)-3-Methoxydecanol Proposed bioreduction route Sample passes Further process Customer Analysis optimisation PCDPoC Demons tra tion Process Development Tech Transfer & PdProduc tRlt Release 30 g sample sent to Customer kg delivery Scale-up From Almac PoC to Commerical Supply of Building Block t = 0 t = Final Delivery of BB Project siting Customer Decision t = PoC Partner selection To initiate alternative route Completion investigation “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Recombinant CREDs – how they work, and how to work with them: Screening phase: RECYCLE COFACTOR REDUCTION o Identify catalyst, o Identify co-factor, Gluconate o Identify recycling pH stat GDH O system. R' R'' Glucose NAD(P)+ ee is what matters! CRED OH NAD(P)H O R' R'' PRD phase – optimise: temperature, pH, CRED o OH co-solvent, enzyme form, catalyst loading, throughput. Cost is what matters! “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Case study: (R)-3-Methoxydecanol Key Step Bioreduction CRED A-161, GDH-102 glucose O O OH O NAD+ C7H15 OMe KH2PO4 buffer C7H15 OMe pH 7.0 5% v/v DMSO CRED Screening: • A161 identified as hit with >99.5% ee • Enzyme is NADH-dependent • GDH/glu cose u sed for co-factor rec ycle Process Optimisation: • 5% DMSO co-solvent, pH 7.0, 30 deg C • 0.1% w/w of lyo cell free extract CRED/GDH sufficient • 180 g/L substrate >99.8% converted within 12 hours • Workup by extraction with MtBE; crude product telescoped into next step “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Case study: (R)-3-Methoxydecanol – impurity control Control of Diol-impurity starts here. OH High reaction completion target C7H15 OH of > 99.8% conversion. Diol-impurity Control of Dec-3-enol impurity starts here. High reaction completion targets. Choice of base for deprotonation. C7H15 OH Unstabilised THF used for methylation. Decenol-impurity Fractional distillation in both final steps. Achieved: 99.3% ee; diol <0.2%; dec-2-enol <0.15% BHT and Me-BHT <0.2%, all other <0.1%. “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Case study: (R)-3-Methoxydecanol from POC sample to commercial output 5 Step Process Yields (%POC / %pilot batch / %final) Step 1: 75% / 50% / 85% Step 2: 91% / 90% / 95% Step 3: 95% / 95% / 98% Step 4: 80% / 70% / 85% Step 5: 70% / 70% / 75% Process modifications after pilot batch experience: Step 1: switched from Meldrum’ s acid to methyl potassium malonate SM Step 4: switched from n-BuLi to n-HexLi, relaxed specification Step 5: improved hydrolysis protocol “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Case study: (R)-3-Methoxydecanol Summary • 5-Step process (()one biotransformation) • Asymmetric chemo-cat route not viable • Biocatalyst far cheaper and giving superior selectivity • Biocatalyst was off-the-shelf, facilitating rapid identification and PRD • Enzyme or ig ina lly foun dthd throug h genome m in ing, an dthd then expressed in E. coli • Improved route design and simplified purification strategy to deliver better quality at higher yield • POC sample followed by 25 kg pilot batch • Several full scale campaigns split between Almac and two partners with equivalent distillation capability “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] What do these molecules have in common? Me Et NH2 NH2 H2N CO2H OH They are in demand as pharmaceutical intermediates. Almac chemists have worked on scaleable syntheses. They are very small molecules with even smaller substituent difference at the stereocentre = tricky to make. Chiral technology cost contribution is high due to low MW. We had some success,,q but further work is required. “From Genomes to Biotransformation Scale Up”, Burlington House, London, 05 November 2014 [email protected] Mature enzyygpme technologies example: Applications of Hydrolases Kinetic resolution Desymmetrization : : O O O S + S S CO R 2 1 R2 R2 R2 CO2H CO2R1 R 2 R2 R2 + R CO R 3 2 1 R3 CO2H R3 CO2R1 + CO2R CO H 2 CO2R 50% y ie ld 100% yield “From
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