MASTER 2 Molecular Chemistry – Medicinal Chemistry Université de Rennes 1 – Vietnam National University, Hanoi SYNTHESIS OF COMMERCIAL DRUGS COMMERCIAL DRUGS Prof. Pierre van de Weghe e-mail : pierre.van-de-weghe@univ-rennes1.fr 2011-2012 CO 2 EtO N H 2 . H 3 P O 4 AcHN N N N H N HN O N N M e .CH 3 SO 3 H O H O N H 2 N S C O 2 M e Cl . H 2 S O 4 N H N S N MeO M e O M e Me O INTRODUCTION 2 Chem. Rev. 2006, 106 , 3002. SYNTHESIS OF LYRICA (pregabalin) Evans diastereoselective alkylation 3 racemic Evans diastereoselective alkylation = a very powerfull tool for asymmetric synthesis O O N O R LDA O O N O R L i always Z ! R 1 X O O N O R R 1 major N O O Li O R Cleavage of the chiral auxiliary R O O N O c a r b o n y l m o r e N O R R 2 R 1 X The addition of the enolate to the electrophile occurs on the less sterically hindered face, that is to say, on the opposite side to the R 2 group of the chiral auxiliary. R 1 O N c a r b o n y l m o r e reactive than a classical amide less reactive center LiBH 4 ou LAH R OH R 1 LiOOH R OH R 1 O HN(OMe)Me R N(OMe)M e R 1 O Evans, D.A. et coll. J. Am. Chem. Soc. 1982, 104, 1737 and lecture of René Grée SYNTHESIS OF LYRICA (pregabalin) 4 SYNTHESIS OF LYRICA (pregabalin) Manufacture route CHO EtO 2 C CO 2 Et n-Pr 2 NH AcOH CO 2 Et C O 2 E t KCN EtOH CO 2 Et C O 2 E t CN Lipolase (8 mol%) pH 7.0 150 nM Ca(OAc) 2 3 M in substrate C O E t C O E t recycling NaOEt, Tol 110 °C (racemization ) C O E t 5 CO 2 Et C O 2 E t CN CO 2 Na C O 2 E t CN >99% ee 85-90% ee not isolated reflux 80 - 85 °C CN CO 2 H 1- KOH - H 2 O 2- Ni sponge (H 2 ) C O 2 E t NH 2 40-45% overall yield after one recycle *All reaction run in aqueous media *Ratio of kg waste/kg pregabalin produced Classical resolution route 86:1 Chemoenzymaticroute 17:1 *Solvent use per 1000 kg pregabalin Classical resolution route 50,042 kg Chemoenzymatic route 6230 kg 99.5% purity 99.75% ee Org. Proc. Res. Dev. 2008, 12 , 392. N Me Me 2 steps N Me Me Me O HNO 3 CH 2 Cl 2 N Me Me Me O N O 2 Na / MeOH reflux N Me Me Me O O M e SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole) N H N S N MeO Me OMe Me O Prilosec (omeprazole) Astra Zeneca (1985) Proton pomp inhibitor used in the treatment of gastric reflux disease Sales 2007 = $5 billion Off patent in 2014 First synthesis : preparation in racemic form O O O Ac 2 O, 100 °C N Me Me OMe OH SOCl 2 N Me Me OMe Cl base N H N MeO SH MeO NH 2 NH 2 EtO SK S NaOH, EtOH, H 2 O reflux, 2 h, 70% N H N MeO S N M e O M e Me mCPBA CHCl 3 N H N MeO S N M e O M e Me O racemic 6 J. Med. Chem. 1992, 35 , 1049. Improvement : omeprazole to esomeprazole 1987 – Prilosec found to display significantly varying efficacy depending on rate of metabolism of patient. Program launch to find a compound with increased bioavailability that won’t be cleared by the liver so quickly to give “slow metabolizers”a chance 1989-1994 – 30 scientists and several hundred compounds later…four candidates are identified Only one compound survives pharmacokinetics, efficacy and safety assessments… esomeprazole, the S-enantiomer of omeprazole. O O Ph O H SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole) 7 N H N MeO S N Me OMe Me O 1- HCHO 2- SOCl 2 3- (R)-mandelic acid NaOH, Bu 4 NHSO 4 CHCl 3 , H 2 O, reflux 38% N N MeO S N Me OMe Me O O 1- separation of diastereomers (preparative HPLC) 2- NaOH, MeOH, H 2 O, rt 3- MgCl 2 , H 2 O N H N MeO S N M e O M e Me O esomeprazole omeprazole Improvement : omeprazole to esomeprazole SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole) Formation of the sulfoxide by using of the Kagan’s oxidation (Sharpless oxidation modified) 8 route steps from sulfur manufacture of esomeprazole (5 kg in plant) medicinal route new route 6 14 weeks 1 2 weeks SYNTHESIS OF LIPITOR (atorvastatin calcium) Chiral side chain : 220 ton / year Cholesterol: a very important biological molecule -most cholesterol is not dietary, it is synthesized internally . internally . -cholesterol is bound to lipoproteins and transported through blood. -2 kinds of lipoproteins: -high density lipoprotein (HDL): “good” - low density lipoprotein (LDL): “bad” atherosclerosis coronary heart disease & other cardiovascular diseases One of the leading causes of death in the world today! 9 [...]... kg scale 13 SYNTHESIS OF LIPITOR (atorvastatin calcium) The enantioselective synthesis of atorvastatin calcium: the solution Synthesis of Paal-Knorr precursor 1 Synthesis of Paal-Knorr precursor 2 14 SYNTHESIS OF LIPITOR (atorvastatin calcium) The enantioselective synthesis of atorvastatin calcium : the solution (2) 15 SYNTHESIS OF TAMIFLU (oseltamivir phosphate) O CO2Et AcHN structure of neuraminidase... CONHPh 1- HPLC separation 2- NaOH 3- H3 O+ 4- Tol, 110 °C Me F N Me Ph Me F N + CONHPh (+ )- atorvastatin lactone IC50 = 0.007 µM Me Ph CONHPh (-) - atorvastatin lactone IC50 = 0.44 µM 12 SYNTHESIS OF LIPITOR (atorvastatin calcium) The enantioselective synthesis of atorvastatin lactone (labor approach) F + CHO CO2Me i-Pr EtO Bn N Cl Me S HO OEt F Ph Et3 N O O HO NaOH, CH3OH O HO Me N Me CONHPh 1- Ot-Bu 2-. . .SYNTHESIS OF LIPITOR (atorvastatin calcium) A solution: the suppression of the cholesterol biosynthesis inhibition 10 SYNTHESIS OF LIPITOR (atorvastatin calcium) The story of statins drugs Potent inhibitors of HMG-CoA reductase 11 SYNTHESIS OF LIPITOR (atorvastatin calcium) The synthesis of atorvastatin lactone Me O O Cl O F Br O NH Et3 N, CH3CN, rt CO2Et O HO O N Tol N 2- NaOH HO2C 1- Bu3B,... CH3OH O HO Me N Me CONHPh 1- Ot-Bu 2- Et3B, NaBH4 3- H2O2 , NaOH 4- Tol, 110 °C O H2N O O Me F N Me Ph N OEt Me TsOH, Tol Ph O O F Ph Ph i-Pr OLi Me F F i-Pr CO2Me O (+ )- atorvastatin lactone (> 99% ee) OEt 1- NBS, DMF 2- nBuLi, THF, PhNCO 3- H3O+ Ph 1- LDA, MgBr2, -7 8 °C OH O Ph Ph OH Ph Me O F Ph Ph O Me N 2- NaOMe, MeOH, 0 ° C CONHPh H Me Ph CONHPh 12 linear steps 3 columns and 1 recrystallization... TMSOTf 6 3-7 5% EtOH aq 96% PMe3 O 80% O CO2Et O 10 / 1 OH CO2Et i) H2, Ra-Ni, ,EtOH ii) H3PO4 AcHN N3 7 1-7 5% O CO2Et AcHN NH2.H3 PO4 - 21% overall yield, 10 steps - industrial synthesis - minor drawback : the sourcing (shikimic acid) - major drawback : the use of azide chemistry 21 SYNTHESIS OF GLIVEC (imatinib) Novartis (2001) Treatment of Chronic Myeloid Leukemia (CML) First protein kinase inhibitor to... Tamiflu Roche (1995) Anti-viral drug to slow the spread of the Influenza virus Sales 2009 = 2.7 billion € Review = Chem Rev 2009, 109, 4398 HO H HO OH AcHN O OH CO2H OH sialic acid (N-acetylneuraminic acid) towards the drug design 16 SYNTHESIS OF TAMIFLU (oseltamivir phosphate) Inhibition of the viral neuraminidase 17 SYNTHESIS OF TAMIFLU (oseltamivir phosphate) Enzymatic mechanism of the viral neuraminidase... kinase (Bcr-Abl) Bcr-Abl) Sales 2007 = $3 billion Off patent in 2015 Cancer Res.2002, 62, 4236 22 SYNTHESIS OF GLIVEC (imatinib) The clinical development was particularly rapid, as can be seen by comparison with the typical drug discovery and development times 23 SYNTHESIS OF GLIVEC (imatinib) Glivec : structure design The phenylaminopyrimidine structure identified - as Protein Kinase C (a serine-theonine... Oseltamivir phosphate: the first synthesis 20 SYNTHESIS OF TAMIFLU (oseltamivir phosphate) Oseltamivir phosphate: the Roche synthesis HO CO2H HO i) EtOH, SOCl2 ii) pentan-3-one, TsOH iii) MsCl, Et3N OH (-) acide shikimique KHCO3, EtOH aq CO2Et HN (74% de pureté) HO CO2Et O HO O CO2Et N3 N3 ii) Ac2 O CO2 Et OMs O NaN3, NH4Cl CO2Et i) NaN3, NH4Cl, DMF 97% O BH3.Me2 S OMs O O TMSOTf 6 3-7 5% EtOH aq 96% PMe3 O 80%... N -spacer inserted to avoid aniline structure -piperazine increases activity, selectivity and water solubility Nature Review Drug Discovery.2002, 1, 493 24 SYNTHESIS OF GLIVEC (imatinib) Glivec : Zimmermann’s route (1993) 25 SYNTHESIS OF GLIVEC (imatinib) Glivec : Loiseleur’s route (2003) – use cross-coupling reaction imatinib base Buchwald-Hartwig cross-coupling reaction 26 ... CONHPh Me Ph Me Ph 1- HCl, EtOH, reflux 2- TsOH, acetone-H2O O Me 2- NaOH, H2O2 CONHPh CO2Me O CHO OMe Me Ph Me Ac2 O, 90 °C Me F NaH N CONHPh N O O CO2Me Me F O HO F atorvastation lactone racemic IC50 = 0.025 mM Ph Me HO Me F N Me then BuLi, THF CONHPh Ph CONHPh racemic Separation of enantiomers (resolution via diastereomeric esters synthesis) H N O HO NHPh CO2Et HO Ph Me O O O F 1- Et3N, CH2Cl2, 0 . – Vietnam National University, Hanoi SYNTHESIS OF COMMERCIAL DRUGS COMMERCIAL DRUGS Prof. Pierre van de Weghe e-mail : pierre.van-de-weghe@univ-rennes1.fr 201 1-2 012 CO 2 EtO N H 2 . H 3 P O 4 AcHN N N N H N HN O N N M e .CH 3 SO 3 H O H O N H 2 N S C O 2 M e Cl . H 2 S O 4 N H N S. scale SYNTHESIS OF LIPITOR (atorvastatin calcium) The enantioselective synthesis of atorvastatin calcium: the solution Synthesis of Paal-Knorr precursor 1 Synthesis of Paal-Knorr precursor 2 14 SYNTHESIS. assessments… esomeprazole, the S-enantiomer of omeprazole. O O Ph O H SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole) 7 N H N MeO S N Me OMe Me O 1- HCHO 2- SOCl 2 3- (R)-mandelic acid NaOH, Bu 4 NHSO 4 CHCl 3 ,