synthesis of the hcv protease inhibitor vaniprevir (mk- 7009) …ccc.chem.pitt.edu/wipf/current...
TRANSCRIPT
Jongrock Kong*, Cheng-yi Chen*, Jaume Balsells-Padros, Yang Cao, Robert F. Dunn,Sarah J. Dolman, Jacob Janey, Hongmei Li, and Michael J. Zacuto
JOC. ASAP. March 29, 2012DOI: 10.1021/JO3001595
Christopher RosenkerWipf Group - Current Literature
April 28, 2012
Synthesis of the HCV Protease Inhibitor Vaniprevir (MK-7009) Using Ring-Closing Metathesis Strategy
NO
O
O
O
HN
N
O
CO2R
NO
O
O
O
HN
N
O
CO2R
N N
RuCl
Cl
O
Grubbs-Hoveydasecond generation
NO
O
O
O
HN
N
OO
HN N
H
OS
O
O
Vaniprevior (MK-7009)9 steps, 55% overall yield
20
Chris Rosenker @ Wipf Group Page 1 of 20 10/12/2014
Hepatitis C Virus (HCV)• 130-170 million people worldwide are affected by Hepatitis C virus (HCV)
• Infection commonly leads to liver diseases including cirrhosis and hepatocellular carcinoma
• Leading cause of death in HIV patients
• Current therapy is pegylated interferon-α and ribavirin
• Weekly injection of interferon; ribavirin orally
• Serious side effects limit patients eligible for treatment
• Therapy duration is dependant on HCV genotype
• genotype 1: ~45% after 48 weeks
• genotype 2 and 3: ~80% after 24 weeks
J. Med. Chem. 2010. 53. 2443.
NN O
NH2
OHO
HO OHRibavirin
N
N
NH2
NH
N
N
NH N NH2
NH
O
N
NH
O
NH2
N
NH
NH2
O
Chris Rosenker @ Wipf Group Page 2 of 20 10/12/2014
Hepatitis C Virus (HCV)Development of NS3/4a protease inhibitors has led to several clinical drug candidates.
J. Med. Chem. 2010. 53. 2443.
NN
NHO HN
O
O
N
H
H
O NHO
O NH
Telaprevir (VX-950)Vertex
(covalent inhibitor)
NMeO N
SNH
O
N
OHNO
O
O
HN CO2H
BILN-2061Boehringer Ingelheim
(rapidly reversible)
NHN
O
ONH2
OO
HN
HN
O
Boceprevir (SCH 503034)Schering-Plough(covalent inhibitor)
O
N
OHNO
O
O
HN
ITMN-191InterMune & Array Biopharma
(rapidly reversible)
O
NH
SO
O
NO
F
O
O
HN
O
NH
SO
O
N N
SMeO
O NMe
TMC-435350Tibotec BVBA & Medivir AB
(rapid reversible)
O
O
HN
N
OO
HN N
H
OS
O
O
Merck(initial lead)
N
O
Chris Rosenker @ Wipf Group Page 3 of 20 10/12/2014
Discovery of Vaniprevir (MK-7009)
Merck’s initial lead was discovered by molecular modeling of therapeutic hits VX-950(Vertex) and BILN-2061 (BI) bound to Hepatitis C NS3/4A Protease.
J. Am. Chem. Soc. 2008, 130, 4607.J. Med. Chem. 2010, 53, 2443.
NO
O
O
O
HN
N
OO
HN N
H
OS
O
O
Vaniprevir (MK-7009)
O
O
HN
N
OO
HN N
H
OS
O
O
Merck(initial lead)
N
O SAR
Chris Rosenker @ Wipf Group Page 4 of 20 10/12/2014
Discovery Synthesis of Vaniprevir (MK-7009)
WO 2011/025849PCT/US2010/046725
PhCHOH2N CO2Et
TEA, MeCNN CO2EtPh
97%
H2N CO2Et
65% overtwo steps
1. t-BuOLi, toluene
2. 3M HCl, toluene
Br Br
85%
Boc2O
Alcalase, buffer pH 8
15% v/v DMSO
BocHN CO2Et
47%>99% ee
50 wt% NaOH
MeOH, 40 °C
BocHN CO2HCDI, DBU
i-PrOAc, 40
BocHN
OSO
H2N
NH
OS
O
O
92% overtwo steps
5% Ru/C, MeOH
H2 (50 psi)
BocHN NH
OS
O
O
90%99% ee
TsOH, PrOH
60 °C
H2N NH
OS
O
O
74%99% ee
TsOH
BocHN CO2Et
Side chain synthesis: Reported on multi-kilogram scale, 9 steps, 15% yield
Chris Rosenker @ Wipf Group Page 5 of 20 10/12/2014
Discovery Synthesis of Vaniprevir (MK-7009)
J. Med. Chem. 2010. 53. 2443.
Br
1. NBS, (PhCO2)2 CCl4, reflux (92%)
2. K2CO3, BnNH2 MeCN, 77 °C (50%)
Cl
O
O
Cl
3. Bu3SnCH=CH2, Pd(PPh3)4 toluene, 100 °C (83%)
4. DCE, reflux,
then MeOH, reflux (86%)Br
NBn NH
A
O
O
HN
OH
O
B
OH
triphosgene, DIPEAdioxane, rt; then 0 °C
1N NaOH,H2N
OH
O
(85%)
1. CDI, DMF; then A, 60 °C (81%)
2. HCl, dioxane (90%)NBoc
CO2Me
HO
NO
O NH2Cl
CO2MeB, HATU
DIPEA, DMF
(91%)
NO
O
O
O
HN
N
O
CO2Me
Chris Rosenker @ Wipf Group Page 6 of 20 10/12/2014
Discovery Synthesis of Vaniprevir (MK-7009)
J. Med. Chem. 2010. 53. 2443.
NO
O
O
O
HN
N
O
CO2Me
N N
RuCl
Cl
O SN
O O
10 mol% Zhan 1BCH2Cl2, 3mM, rt (98%)
1. H2, 10% Pd/C EtOH, EtOAc
2. LiOH•H2O, THF MeOH
NO
O
O
O
HN
N
O
CO2H HATU, DIPEADMAP, CH2Cl2(91%, 3 steps)
ClH3N NH
OS
O
ON
O
O
O
O
HN
N
OO
HN N
H
OS
O
O
Vaniprevir (MK-7009)11 steps LLS, 19% yield
NO
O
O
O
HN
N
O
CO2Me
Chris Rosenker @ Wipf Group Page 7 of 20 10/12/2014
Synthesis of Vaniprevir (MK-7009): Route Improvement
J. Org. Chem. 2011, 76, 7804.
NO
O
O
O
HN
N
O
CO2Me
Amide BondFormation
RCM
C-C BondFormation
NO
O
O
O
HN
N
O
CO2Me
Zhan 1B (10 mol%)98% or
Neolyst M1 (30 mol%)91%, <3 mM
NO
O
O
O
HN
N
O
CO2Me
RuPCy3
PCy3 PhClCl
Macrocylization using RCM
Possible Macrocylization Strategies• Ring Closing Metathesis• Metal-mediated C-C• Amide Bond Formation
• Requires rigorous purification of diene• High catalyst loading• High reaction concentration
• Incomplete conversion• Difficult catalyst removal process• Catalyst cost
Chris Rosenker @ Wipf Group Page 8 of 20 10/12/2014
Synthesis of Vaniprevir (MK-7009): Metal-mediated C-C
J. Org. Chem. 2011, 76, 7804.
NO
O
Br
O
O
HN
N
O
CO2MePd(II), K2CO3, Bu4NHCl
toluene (8mg/mL), 100 °C
NO
O
O
O
HN
N
O
CO2Me
47%9-BBN
NO
O
Br
O
O
HN
N
O
CO2MeBR2 PdCl2(DPPF), NaOH
THF (7mg/mL), 40 °C
NO
O
O
O
HN
N
O
CO2Me
~5%
NO
O
Br
O
O
HN
N
O
CO2MePdCl2(Xphos)
Cs2CO3, MeCN (5mg/mL)
NO
O
O
O
HN
N
O
CO2Me
~35%
Heck
Suzuki
Sonogashira
Chris Rosenker @ Wipf Group Page 9 of 20 10/12/2014
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
NH
OH
CO2MeO
Coupling Reagents
Solvent, i-Pr2NEt
X NN
N
O P NN
NPF6
PF6N
NN
ON
NPF6
HBTU (X = CH) 60%HATU (X = N) 75%
pyBOP (X = CH) 64%pyAOP (X = N) 79%
BOP62%
HBPYU50%
Uronium Derived Reagents and Cyclization Yields
EDC + Additive and Yields
N NN
OOH
N OHO
N
NN
NOH
NN
NOH
HBTO76%
HOPO74%
HOAt66%
HOBt66%
X NN
N
ON
N
PF6
NN
N
ON
NPF6
HCTU60%
Cl NN
N
O P NN
N
Synthesis of Vaniprevir (MK-7009): Amide Bond Formation
J. Org. Chem. 2011, 76, 7804.Chris Rosenker @ Wipf Group Page 10 of 20 10/12/2014
Title Paper: Vaniprevir (MK-7009) using RCM
J. Org. Chem. 2012, ASAP. doi: 10.1021/jo3001595
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
N
OO
HN N
H
OS
O
O
Vaniprevir (MK-7009)
RCMHydrogenation
H2N NH
OS
O
O
Chris Rosenker @ Wipf Group Page 11 of 20 10/12/2014
Title Paper: Vaniprevir (MK-7009) using RCM
J. Org. Chem. 2012, ASAP. doi: 10.1021/jo3001595
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
N
O
CO2Me
high cat. loadingreproducabiltiy issues
SM not readily available/cost efficiency concerns
Chris Rosenker @ Wipf Group Page 12 of 20 10/12/2014
Title Paper: Vaniprevir (MK-7009) using RCM
J. Org. Chem. 2012, ASAP. doi: 10.1021/jo3001595
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
N
OO
HN N
H
OS
O
O
Vaniprevir (MK-7009)
RCMHydrogenation
H2N NH
OS
O
O
NO
O
O
O
HN
N
O
CO2Me
NH
CDI-MediatedCarbamate Formation
O
O
HN
N
O
CO2Me
HO
NH
CO2Me
HO
EDC-MediatedAmide Bond Formation
O
O
HN
OH
O
Chris Rosenker @ Wipf Group Page 13 of 20 10/12/2014
Title Paper: Preparation of Macrocycle Precursor
J. Org. Chem. 2012, ASAP. doi: 10.1021/jo3001595
Br
CN LDA, -70 °C;EtOCOH
Br
CN
OLi
OEt
Br
NH
OH
O
Br
NH
1. BH3•Me2S toluene, reflux
2. HCl, i-PrOH•HCl NH•HCl
1% Pd(OAc)2
2% (Np)t-Bu2P•HBF4THF:PhMe (2.5:1)
40 °C84% overtwo steps
MgCl
90%
O O
ON N
O
O O
O
(DSC)Pyridine (20%)
DMF, 50 °C
O
O
HN
H2N CO2H
DMF-H2O, NaHCO3rt
94% overtwo steps
$1.10/gOakwoodProducts
CO2Me1. LDA, -78 °C
2. LAH, Et2O 0 °C
Br
71% overtwo steps$0.12/mL
TCI America
CO2H
EDC•pyridineDIPEA, MeCN
NH
CO2Me
HO
•HClO
O
HN
N
O
CO2Me
HO
NH•HCl
N N
O
NN
NO
O
O
O
HN
N
O
CO2Me
97%
95%
OHO
O
ON
O
O
Chris Rosenker @ Wipf Group Page 14 of 20 10/12/2014
Title Paper: RCM Optimization
J. Org. Chem. 2012, ASAP. doi: 10.1021/jo3001595
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
N
O
CO2Me
N N
RuCl
Cl
O
1. Toluene (50 mL/g), 60 °C
2. H2, Pd/C (20 wt%)
Addition modeone-pot
one-pot
slow additionof cat.
Cat. Loading1 mol%
5 mol%
1 mol%
Yield57%
67%
82%
• Optimization 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• Oligomer formation occurred towards the end of the reaction
Chris Rosenker @ Wipf Group Page 15 of 20 10/12/2014
Title Paper: RCM Optimization
J. Org. Chem. 2012, ASAP. doi: 10.1021/jo3001595
• Attempts to increase concentration of diene led to undesired 19-membered ring• Ru-H complex generated by decomposition of GH-2G is responsible for isomerization
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
N
O
CO2Me
N N
RuCl
Cl
O
Rxn Conditions
1 mol% Ruslow addition over1 h, toluene, 60 °C
Volume Ratio(mL/g SM)
50
30
Results
NO
O
O
O
HN
N
O
CO2Me20 19
20-mac
82%
61%
19-mac
<1%
9%
NO
O
O
O
HN
N
O
CO2Me
RCM
[Ru-H]SM
GH-2G
Chris Rosenker @ Wipf Group Page 16 of 20 10/12/2014
Title Paper: RCM Optimization
J. Org. Chem. 2012, ASAP. doi: 10.1021/jo3001595
• Ru-H complex mediated isomerization can be suppressed by addition of quinone additives• Lower cat. loading, higher temperature increased yield• Removal of ethylene by subsurface N2 bubbling increased yield slightly• Simultaneous addition of diene and cat. mimic high dilution allowing increased overallconcentration and yield.
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
N
O
CO2Me
N N
RuCl
Cl
O
slow addition of cat. over 1 h, toluene
additive (10 mol%)
20
NO
O
O
O
HN
N
O
CO2Me19
Entry123456
mol% cat.1
0.20.20.20.20.2
Temp (°C)7070100100100100
Additivenone
2,6-dichloroquinone2,6-dichloroquinone2,6-dichloroquinone2,6-dichloroquinone2,6-dichloroquinone
Conc. (ml/g)20202020
13.513.5
Results20-ring
627284887891
19-ring8
<11.51.522
dimers/oligomers5555
>155
MethodAAABBC
Method A: no additional operationMethod B: subsurface N2 gas bubblingMethod C: simultaneous addtion of diene substrate
Chris Rosenker @ Wipf Group Page 17 of 20 10/12/2014
Title Paper: Saturated Macrocycle
J. Org. Chem. 2012, ASAP. doi: 10.1021/jo3001595
• Successfully performed preparation of saturated macrocycle on 100 g scale• Found RCM to be sensitive to impurities, not acceptable for robust manufacturing process• Oily diene precursor not amenable to crystallization
NO
O
O
O
HN
N
O
CO2Me
NO
O
O
O
HN
N
O
CO2Me
30 wt% of 5% Pd/CH2 (45 psi), toluene
i-PrOH, 1h
89%(>99% purity by HPLC)
(1 RXC from i-PrOH/water<10 ppm Ru & Pd)
Chris Rosenker @ Wipf Group Page 18 of 20 10/12/2014
Title Paper: Second-Generation RCM Strategy
J. Org. Chem. 2012, ASAP. doi: 10.1021/jo3001595
Second-generation strategy provides a robust manufacturing route
NO
O
O
O
HN
N
O
CO2Me
KOH (powder)i-PrOH
NO
O
O
O
HN
N
OO
OK
92%crystalline solid
(>97% pure by HPLC)
15% citric acidtoluene
NO
O
O
O
HN
N
OO
OH
>99%toluene stock solution(>97% pure by HPLC)
0.2 mol% GH-2G2,6-dichlororquinone (10 mol%)
toluene (13.5 mL/g diene)
(simultaneous slow addition ofcat. & diene over 1 h)
NO
O
O
O
HN
N
O
91%
OH
O
NO
O
O
O
HN
N
O
OK
O
1. 30 wt% of 5% Pd/C H2 (45 psi), toluene, i-PrOH, 1h
2. KOH, EtOH, 45 °C, 1h
82% overtwo steps
(<92% pure by HPLC)
Chris Rosenker @ Wipf Group Page 19 of 20 10/12/2014
Title Paper: Synthesis of Vaniprevir (MK-7009)
J. Org. Chem. 2012, ASAP. doi: 10.1021/jo3001595
NO
O
O
O
HN
N
O
OK
O
H2N NH
OS
O OTsOH
1. EDC, pyridine MeCN, i-PrOAc
2. cyrstallization i-PrOAc/heptane
NO
O
O
O
HN
N
O
HN
O
O
NH
SO O
Vaniprevir (MK-7009)84%
• Successful optimization of RCM strategy to give macrocycle in high yield and purity usinglow 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 LLS)
Chris Rosenker @ Wipf Group Page 20 of 20 10/12/2014