Synthesis of the HCV Protease Inhibitor Vaniprevir (MK- 7009) Using Ring-Closing Metathesis Strategy
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1 ynthesis of the CV Protease Inhibitor Vaniprevir (MK- 7009) Using Ring-osing Metathesis trategy Jongrock Kong*, Cheng-yi Chen*, Jaume Balsells-Padros, Yang Cao, Robert F. Dunn, arah J. Dolman, Jacob Janey, ongmei Li, and Michael J. Zacuto JC. AAP. March 29, 2012 DI: /J Ru C 2 R Grubbs-oveyda second generation 20 C 2 R Vaniprevior (MK-7009) 9 steps, 55% overall yield Christopher Rosenker Wipf Group - Current Literature April 28, 2012 Chris Wipf Group Page 1 of 20 10/12/2014
2 epatitis C Virus (CV) million people worldwide are affected by epatitis C virus (CV) Infection commonly leads to liver diseases including cirrhosis and hepatocellular carcinoma Leading cause of death in IV patients Current therapy is pegylated interferon-α and ribavirin Weekly injection of interferon; ribavirin orally erious side effects limit patients eligible for treatment Therapy duration is dependant on CV genotype J. Med. Chem genotype 1: ~45% after 48 weeks genotype 2 and 3: ~80% after 24 weeks Ribavirin Chris Wipf Group Page 2 of 20 10/12/2014
3 epatitis C Virus (CV) Development of 3/4a protease inhibitors has led to several clinical drug candidates. Me BIL-2061 Boehringer Ingelheim (rapidly reversible) C 2 Telaprevir (VX-950) Vertex (covalent inhibitor) Boceprevir (C ) chering-plough (covalent inhibitor) 2 F Me Me ITM-191 InterMune & Array Biopharma (rapidly reversible) J. Med. Chem TMC Tibotec BVBA & Medivir AB (rapid reversible) Merck (initial lead) Chris Wipf Group Page 3 of 20 10/12/2014
4 Discovery of Vaniprevir (MK-7009) Merck s initial lead was discovered by molecular modeling of therapeutic hits VX-950 (Vertex) and BIL-2061 (BI) bound to epatitis C 3/4A Protease. AR Merck (initial lead) Vaniprevir (MK-7009) J. Am. Chem. oc. 2008, 130, J. Med. Chem. 2010, 53, Chris Wipf Group Page 4 of 20 10/12/2014
5 Discovery ynthesis of Vaniprevir (MK-7009) ide chain synthesis: Reported on multi-kilogram scale, 9 steps, 15% yield PhC 2 C 2 Et TEA, MeC Ph 97% 1. t-buli, toluene C 2 Et 2. 3M, toluene 2 C 2 Et Boc 2 Boc C 2 Et 65% over two steps 85% Alcalase, buffer p 8 15% v/v DM Boc 47% >99% ee C 2 Et 50 wt% a Me, 40 C Boc C 2 CDI, DBU i-prac, 40 2 Boc 92% over two steps 5% Ru/C, Me 2 (50 psi) Boc Ts, Pr 60 C Ts 2 90% 99% ee 74% 99% ee W 2011/ PCT/U2010/ Chris Wipf Group Page 5 of 20 10/12/2014
6 Discovery ynthesis of Vaniprevir (MK-7009) 1. B, (PhC 2 ) 2 C 4, reflux (92%) 2. K 2 C 3, Bn 2 MeC, 77 C (50%) Bn 3. Bu 3 nc=c 2, Pd(PPh 3 ) 4 toluene, 100 C (83%) 4. DCE, reflux, then Me, reflux (86%) A triphosgene, DIPEA dioxane, rt; then 0 C 1 a, 2 B (85%) Boc C 2 Me 1. CDI, DMF; then A, 60 C (81%) 2., dioxane (90%) C 2 Me 2 B, ATU DIPEA, DMF (91%) C 2 Me J. Med. Chem Chris Wipf Group Page 6 of 20 10/12/2014
7 Discovery ynthesis of Vaniprevir (MK-7009) Ru 10 mol% Zhan 1B C 2 2, 3mM, rt (98%) 1. 2, 10% Pd/C Et, EtAc C 2 Me C 2 Me 2. Li 2, TF Me 3 C 2 ATU, DIPEA DMAP, C 2 2 (91%, 3 steps) Vaniprevir (MK-7009) 11 steps LL, 19% yield J. Med. Chem Chris Wipf Group Page 7 of 20 10/12/2014
8 ynthesis of Vaniprevir (MK-7009): Route Improvement C-C Bond Formation RCM C 2 Me Amide Bond Formation Possible Macrocylization trategies Ring osing Metathesis Metal-mediated C-C Amide Bond Formation Macrocylization using RCM Zhan 1B (10 mol%) 98% or C 2 Me eolyst M1 (30 mol%) 91%, <3 mm PCy 3 Ru PCy 3 Ph C 2 Me Requires rigorous purification of diene igh catalyst loading igh reaction concentration Incomplete conversion Difficult catalyst removal process Catalyst cost J. rg. Chem. 2011, 76, Chris Wipf Group Page 8 of 20 10/12/2014
9 ynthesis of Vaniprevir (MK-7009): Metal-mediated C-C Pd(II), K 2 C 3, Bu 4 C 2 Me toluene (8mg/mL), 100 C eck C 2 Me 9-BB 47% BR 2 C 2 Me Pd 2 (DPPF), a TF (7mg/mL), 40 C uzuki C 2 Me Pd 2 (Xphos) ~5% C 2 Me Cs 2 C 3, MeC (5mg/mL) onogashira C 2 Me J. rg. Chem. 2011, 76, Chris Wipf Group Page 9 of 20 10/12/2014 ~35%
10 ynthesis of Vaniprevir (MK-7009): Amide Bond Formation Coupling Reagents C 2 Me olvent, i-pr 2 Et C 2 Me Uronium Derived Reagents and Cyclization Yields PF 6 X PF 6 X P PF 6 PF 6 P PF 6 CTU 60% BTU (X = C) 60% ATU (X = ) 75% pybp (X = C) 64% pyap (X = ) 79% BP 62% BPYU 50% BT 76% EDC + Additive and Yields P 74% At 66% Bt 66% J. rg. Chem. 2011, 76, Chris Wipf Group Page 10 of 20 10/12/2014
11 Title Paper: Vaniprevir (MK-7009) using RCM J. rg. Chem. 2012, AAP. doi: /jo C 2 Me C 2 Me Vaniprevir (MK-7009) RCM ydrogenation 2 Chris Wipf Group Page 11 of 20 10/12/2014
12 Title Paper: Vaniprevir (MK-7009) using RCM J. rg. Chem. 2012, AAP. doi: /jo C 2 Me C 2 Me C 2 Me C 2 Me C 2 Me C 2 Me high cat. loading reproducabiltiy issues M not readily available/ cost efficiency concerns Chris Wipf Group Page 12 of 20 10/12/2014
13 Title Paper: Vaniprevir (MK-7009) using RCM RCM ydrogenation C 2 Me 2 Vaniprevir (MK-7009) C 2 Me CDI-Mediated Carbamate Formation C 2 Me C 2 Me EDC-Mediated Amide Bond Formation J. rg. Chem. 2012, AAP. doi: /jo Chris Wipf Group Page 13 of 20 10/12/2014
14 Title Paper: Preparation of Macrocycle Precursor $1.10/g akwood Products 94% over two steps C C 2 Me $0.12/mL TCI America LDA, -70 C; EtC C 2 C Et Li 1. LDA, -78 C 2. LA, Et 2 0 C C 2 Me EDC pyridine DIPEA, MeC 71% over two steps 1. B 3 Me 2 toluene, reflux 2., i-pr (DC) Pyridine (20%) DMF, 50 C 97% 84% over two steps C 2 Me Mg 1% Pd(Ac) 2 2% (p)t-bu 2 P BF 4 TF:PhMe (2.5:1) 40 C 2 90% C 2 DMF- 2, ac 3 rt C 2 Me 95% J. rg. Chem. 2012, AAP. doi: /jo Chris Wipf Group Page 14 of 20 10/12/2014
15 Title Paper: RCM ptimization Ru 1. Toluene (50 ml/g), 60 C C 2 Me 2. 2, Pd/C (20 wt%) C 2 Me Addition mode one-pot one-pot slow addition of cat. Cat. Loading 1 mol% 5 mol% 1 mol% Yield 57% 67% 82% ptimization goals are cost motivated: low cat. loading, high concentration, high yield Initial test reaction indicated significant optimization required Reaction profiling indicated high catalytic activity at the beginning of the reaction Catalyst activity diminished as reaction proceeded ligomer formation occurred towards the end of the reaction J. rg. Chem. 2012, AAP. doi: /jo Chris Wipf Group Page 15 of 20 10/12/2014
16 Title Paper: RCM ptimization Attempts to increase concentration of diene led to undesired 19-membered ring Ru- complex generated by decomposition of G-2G is responsible for isomerization Ru C 2 Me G-2G C 2 Me C 2 Me Rxn Conditions 1 mol% Ru slow addition over 1 h, toluene, 60 C Volume Ratio (ml/g M) Results 20-mac 19-mac 82% <1% 61% 9% M [Ru-] RCM C 2 Me J. rg. Chem. 2012, AAP. doi: /jo Chris Wipf Group Page 16 of 20 10/12/2014
17 Title Paper: RCM ptimization Ru C 2 Me slow addition of cat. over 1 h, toluene additive (10 mol%) 20 C 2 Me 19 C 2 Me Entry mol% cat Temp ( C) Method A A A B B C Additive Conc. (ml/g) none 20 2,6-dichloroquinone 20 2,6-dichloroquinone 20 2,6-dichloroquinone 20 2,6-dichloroquinone ,6-dichloroquinone ring Results 19-ring dimers/oligomers 8 5 < > Method A: no additional operation Method B: subsurface 2 gas bubbling Method C: simultaneous addtion of diene substrate Ru- complex mediated isomerization can be suppressed by addition of quinone additives Lower cat. loading, higher temperature increased yield Removal of ethylene by subsurface 2 bubbling increased yield slightly imultaneous addition of diene and cat. mimic high dilution allowing increased overall concentration and yield. J. rg. Chem. 2012, AAP. doi: /jo Chris Wipf Group Page 17 of 20 10/12/2014
18 Title Paper: aturated Macrocycle 30 wt% of 5% Pd/C 2 (45 psi), toluene C 2 Me i-pr, 1h C 2 Me 89% (>99% purity by PLC) (1 RXC from i-pr/water <10 ppm Ru & Pd) uccessfully performed preparation of saturated macrocycle on 100 g scale Found RCM to be sensitive to impurities, not acceptable for robust manufacturing process ily diene precursor not amenable to crystallization J. rg. Chem. 2012, AAP. doi: /jo Chris Wipf Group Page 18 of 20 10/12/2014
19 Title Paper: econd-generation RCM trategy C 2 Me K (powder) i-pr K 15% citric acid toluene (<92% pure by PLC) 92% crystalline solid (>97% pure by PLC) >99% toluene stock solution (>97% pure by PLC) 0.2 mol% G-2G 2,6-dichlororquinone (10 mol%) toluene (13.5 ml/g diene) (simultaneous slow addition of cat. & diene over 1 h) wt% of 5% Pd/C 2 (45 psi), toluene, i-pr, 1h 2. K, Et, 45 C, 1h K 91% 82% over two steps econd-generation strategy provides a robust manufacturing route J. rg. Chem. 2012, AAP. doi: /jo Chris Wipf Group Page 19 of 20 10/12/2014
20 Title Paper: ynthesis of Vaniprevir (MK-7009) K Ts 2 1. EDC, pyridine MeC, i-prac 2. cyrstallization i-prac/heptane Vaniprevir (MK-7009) 84% uccessful optimization of RCM strategy to give macrocycle in high yield and purity using low catalyst loading (0.2 mol%) and high overall concentration (0.13 M). Developed a robust manufacturing synthesis of Vaniprevir (MK-7009) in 55% overall yield (9 LL) J. rg. Chem. 2012, AAP. doi: /jo Chris Wipf Group Page 20 of 20 10/12/2014
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