Theory of Occupational Adaptation Schultz, 2009 Schkade & Schultz, 1992
Plugin Schultz Sem
Transcript of Plugin Schultz Sem
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Process Chemistry: From Millimole to KilomoleKevin P. SchultzNelsen GroupApril 6, 2006
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OutlineWhat is Process Chemistry?
Drug Development Timeline and Cost
General Considerations
Emend®From Discovery to Scale-Up
Conclusion
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What is Process Chemistry?
N
O O
N
Cl
Claritin®Schering-Plough
HN
O
N
CO2
HO
HO
F
Lipitor®Pfizer
HN
HN NO
N
O O
F
CF3
CF3
Emend®Merck
HN
Cl
Cl
HCl
Zoloft®Pfizer
SafeEnvironmentally friendly
Efficient Economical ($ and atom)
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Process Chemistry
“Process Chemistry is usually equated with scale-up, but characterizing process chemistry simply as the scale-up of a synthetic route does a grave disservice to the organic chemists who have chosen to focus their creative efforts in this field.”
- Celia M. Henry, Senior Editor
C&E News
Henry, C. M. C&E News May 26, 2002, pg 53-66.
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Drug Development TimelineAverage of 12-15 yrs
Target Screen(s) Hit
LeadCandidate Launch
PatentExpiration
P A T E N T
D I S C O V E R Y
C L I N I C A L
SAFETY/PHARMACEUTICAL STUDIES
P R O C E S S R E S E A R C H
4.5 yrs 2 yrs200-300 gms < 100 kg 100-2000 kg
8.2 years
Gadamasetti, Kumar G. Process Chemistry in the PharmaceuticalIndustry. Marcel Dekker, Inc. New York: 1999.
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Total Drug Development Cost$400 - $800 million per approved drug
DeMasi, J. A. et al. J. Health Economics 2003, 22, 51–185.
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Patent protection for 20 years
Need For Efficient Process Chemistry
http://www.fda.gov/cder/index.html
Generic drug application: Abbreviated New Drug Application (ANDA)
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Presidential Green Chemistry Challenge Award
Established in 1995 by the EPAFor innovations in cleaner, cheaper and smarter chemistry
www.epa.gov/greenchemistry/presgcc.htmlhttp://pubs.acs.org/cen/coverstory/8026/8026greenchemistry.html
HN
N
O
H2N
N
N
OOH
HO
Cytovene®2000 Roche Corp.
Reduced liquid waste: 1120 metric tons / yearReduced solid waste: 25 metric tons / year
HN
Cl
Cl
HCl
Zoloft®2002 Pfizer, Inc.Reduced waste:
HCl (conc): 150 metric tons / yearTiO2: 440 metric tons / year
HN
HN NO
N
O O
F
CF3
CF3
Emend®2005 Merck
Reduced waste:340,000 L / metric ton
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OutlineWhat is Process Chemistry?
Drug Development Timeline and Cost
General Considerations
Emend®From Discovery to Scale-Up
Conclusion
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General Considerations for Process ChemistryAvoid column chromatography
Seeding helps crystallization
Avoid desiccants, use azeotrope
Avoid solvents with flash point < 15 ºCEther, hexanes, DCM
Temperature range -40 to 120 ºC
Avoid protecting groups
Impurities of > 0.1% must be analyzed
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OutlineWhat is Process Chemistry?Drug Development Timeline and CostGeneral ConsiderationsEmend®
Discovery SynthesisRefined Process Chemistry Route2nd Generation SynthesisCommercial Synthesis
Conclusion
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Emend® - Aprepitant
hNK1 receptor antagonist (IC50 = 0.09 nM)1
Treatment of chemotherapy-induced emesis2
FDA approval in 20032005 Presidential Green Chemistry Challenge Award3
Entered preclinical trials in 19931
1 Hale, J. J. et al; J. Med. Chem. 1998, 41, 4607-4614. 2 Rupniak, N. M. et al; Eur. J. Pharmacol. 1997, 326, 201-209.3 http://www.epa.gov/greenchemistry/past.html
HNNH
N
O
CF3
CF3
O
N
O
F
2
3
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O
N
O
CF3
CF3
F
Me
HN
HN NO
O
NH
O
CF3
CF3
F
Me
O NH
O
N
H2NCl
O
N
O
Ph
CF3
CF3
F
Me
O
N
O
Ph
H2C
CF3
CF3
F
O
N
O
Ph
O
CF3
CF3
F
O
N
O
Ph F
Discovery Synthesis Route
Hale, J. J. et al; J. Med. Chem. 1998, 41, 4607-4614.
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OHO
F
ONH
O
Ph
ON
F
OO
Ph
83%
1) KHMDS
ON
OO
Ph
F
N3
67%92% de
S
2) O
O
N3
1) LiOH2) HCl3) H2, Pd/C
F
H2N
OHOPhCHONaOHNaBH4
F
HN
OHO
Ph
BrBr
(i-Pr)2NEtDMF
F
N
OO
Ph74% (two steps)92% ee
1)
2) HCl
Discovery Synthesis: Oxazinone
40% overall yieldHale, J. J. et al. J. Med. Chem. 1996, 39, 1760-1762.
Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011-4030
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OH
NH
Ph
F
O
H
Na2S2O5,NaCN
H2O, MeOH
F
CN
N
HO
Ph
HCl(g)
F
N
Ph
O NH
HCl
1.2 eq H2O
F
N
Ph
O O
HClKHCO3
F
N
Ph
O O
in i-PrOAc
racemate
1)
2)
One-Pot Synthesis of Oxazinone
> 1.2 eq H2O
F
N
Ph
HO OHO
- Washed aminonitrile with 15 wt % NaCl
Nelson, T. D.; Bhupathy, M. European Patent 1112259, 2001.
80% yield
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Dynamic Resolution
N
Ph
(S)
F
O O1.2 eq
SO3H
O
Br
(-) - BCSA
i-PrOAc, refluxN
Ph
(S)
F
O O
BCSA
99% de90% yield
N
Ph
(R)
F
O O
NH3toluene
N
Ph
(S)
F
O O
BSCA NH4i-PrOAc, HCl
Alabaster, R. J.; Gibson, A. W.; Johnson, S. A.; Edwards, J. S.;Cottrell, I. F. Tetrahedron: Asymmetry 1997, 8, 447-450
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O
N
O
CF3
CF3
F
Me
HN
HN NO
O
NH
O
CF3
CF3
F
Me
O NH
O
N
H2NCl
O
N
O
Ph
CF3
CF3
F
Me
O
N
O
Ph
H2C
CF3
CF3
F
O
N
O
Ph
O
CF3
CF3
F
O
N
O
Ph F
Discovery Synthesis Route
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Acyl Acetal Formation
F
(S)
N
Ph
O O
F
N
Ph
O O
F
N
Ph
OO H
F
N
Ph
O O
> -60 oC
CF3
CF3Cl
O
< -60 oC
F
(S)(R)
N
Ph
O O
O
CF3
CF3
99% de82% yield
CF3
CF3Cl
OF
(S)(S)
N
Ph
O O
O
CF3
CF3
L-SelectrideTHF/toluene> -60 oC
L-SelectrideTHF/toluene< -60 oC
strict cryogenic temperatures
Ashwood, M. S.; Cottrell, I. F.; Davies, A. J. Tetrahedron: Asymmetry 1997, 8, 957.
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O
N
O
CF3
CF3
F
Me
HN
HN NO
O
NH
O
CF3
CF3
F
Me
O NH
O
N
H2NCl
O
N
O
Ph
CF3
CF3
F
Me
O
N
O
Ph
H2C
CF3
CF3
F
O
N
O
Ph
O
CF3
CF3
F
O
N
O
Ph F
Discovery Synthesis Route
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TiCl
Cl
MeMgClTi
Me
Me
heat
-CH4Ti CH2
TiMe
Me
energeticdecomposition
decomposes insolid state
-5 to -10 oC
titanium carbenereactive and unstable
O
R OR'
R OR'
TiO
Cp Cp
CH2
R OR'
TiO
Petasis Reagent
>2 eq of Petasis reagent necessary
Petasis Reagent
TiMe
Meexcess
TiO
Ti
major byproduct
TiCl
Cl
HCl
recycle
Ti CH2
undesiredproducts
excess
Hughes, D. L.; Payack, J. F.; Cai, D.; Verhoeven, T. R.; Reider, P. J. Organometallics 1996, 15, 663.Payack, J. F. et al Org. Proc. Res. Develop. 2004, 8, 256.
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Sacrificial Ester
TiMe
Me
F
(S)(R)
N
Ph
O O
O
CF3
CF3
F
(S)(R)
N
Ph
O O
CF3
CF3
Ti
O
Cp
Cp
F
(S)(R)
N
Ph
O O
H2C
CF3
CF3
Ti
92%
80 oC
THF/toluene
OTi
O
O
F
(S)(R)
N
Ph
O O
<Ph
O
CF3
CF3
O
OPh0.75 eq
Payack, J. F. et al Org. Proc. Res. Develop. 2004, 8, 256.
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O
N
O
CF3
CF3
F
Me
HN
HN NO
O
NH
O
CF3
CF3
F
Me
O NH
O
N
H2NCl
O
N
O
Ph
CF3
CF3
F
Me
O
N
O
Ph
H2C
CF3
CF3
F
O
N
O
Ph
O
CF3
CF3
F
O
N
O
Ph F
Discovery Synthesis Route
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Hydrogenation
F
(S)(R)
N
Ph
O O
H2C
CF3
CF3 Pd/Al2O3,H2
F
(S)(R)
N
Ph
O O
(R)
CF3
CF3
F
(S)(R)
N
Ph
O O
(S)
CF3
CF3
+
Me Me
Pd/Al2O3,TsOH, H2
F
(S)(R)
NH
O O
(R)
CF3
CF3Me
F
(S)(R)
NH
O O
(S)
CF3
CF3Me
TsOH TsOH
91 : 9
EtOH:EtOAc1:1
F
(S)(R)
N
O O
CF3
CF3
TsOH
O
86% yield99% de
Nelson, T. D. Synthesis of Aprepitant. Strategies and Tactics in Organic Synthesis;Harmata, M., Ed.; Elsevier: San Diego; 2005: pp 321-351.
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O
N
O
CF3
CF3
F
Me
HN
HN NO
O
NH
O
CF3
CF3
F
Me
O NH
O
N
H2NCl
O
N
O
Ph
CF3
CF3
F
Me
O
N
O
Ph
H2C
CF3
CF3
F
O
N
O
Ph
O
CF3
CF3
F
O
N
O
Ph F
Discovery Synthesis Route
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Triazolinone Ring
F
(S)(R)
NH
O O
(R)
CF3
CF3Me
F
(S)(R)
N
O O
(R)
CF3
CF3Me
NNH
O
H2NO
xylenes140oC
F
(S)(R)
N
O O
(R)
CF3
CF3Me
N
HN
HN
O
aprepitant85%
NH
O
ON
H2N
Cl
K2CO3, toluene, DMSO
- A single SN2 displacement was envisioned- Charcoal treatment
Hale, J. J. et al; J. Med. Chem. 1998, 41, 4607-4614.
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Facile Addition of Triazolinone Ring
commerciallyavailable
HN
NH2
H2N
O
OOO
Cl
MeOH, 20oC
3 days
HN
NH
NO
Cl
90%HCl
F
(S)(R)
NH
O O
(R)
CF3
CF3Me
F
(S)(R)
N
O O
(R)
CF3
CF3
Me
N
HN
HN
O
aprepitant98%
HN
NH
N
ClO
K2CO3, DMF, 1hr, RT
Cowden, C. J. et al Tetrahedron Lett. 2000, 41, 8661.
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1st Generation Synthesis: 1993-199943% overall yield (longest linear sequence)Clinical trials
Larger doses necessary Good results for antiemesisPossible antidepressant
Key improvement areasChiral Acid – BCSA
Expensive (1kg NH4 salt= $4500)Unreacted acid lost
L-SelectrideExpensiveStrict cryogenic temperatures
Dimethyl titanoceneExpensiveToxic
NO NEW IMPURITIES
Nelson, T. D. Synthesis of Aprepitant. Strategies and Tactics in Organic Synthesis;Harmata, M., Ed.; Elsevier: San Diego; 2005: pp 321-351.
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OutlineWhat is Process Chemistry?Drug Development Timeline and CostGeneral ConsiderationsEmend®
Discovery SynthesisRefined Process Chemistry Route3rd Generation SynthesisCommercial Synthesis
Conclusion
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Logical 3rd Generation Retrosynthesis
N
F
O O
CF3
CF3
NNH
HN
O
N
F
O O
CF3
CF3
NNH
HN
OCl
P
CF3
CF3
OH
N
F
O
P
LG
Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747.
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Cis Acetalization Approach
N
O
Ph
O
F
DIBALH
N
O
Ph
OH
F
N
O
Ph
OR
F
1) base
2) RCl
R= C(O)CH3 C(O)CF3 C(NH)CCl3
F3C
CF3
OH
Me
Lewis Acid
N
O
Ph F
O
CF3
CF3
N
O
Ph F
-trans acetalization and elimination products
Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747.Ashwood, M. S.; Cottrell, I. F.; Davies, A. J. Tetrahedron: Asymmetry 1997, 8, 957-963.
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3rd Generation Retrosynthesis
N
F
O O
CF3
CF3
NNH
HN
O
NH
F
O O
CF3
CF3
NNH
HN
O
Cl
N
F
O O
CF3
CF3
N
F
O O
NH
CCl3
Ph
CF3
CF3
OH
N
F
O
Ph
O
F
O
OH
OH
Ph NH
OH
Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747
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F
O
O AcOH /
i-PrOAc
F
O
N
O
(R)
Ph F
(R)
O
N
O
(R)
Ph
2 : 1(3S) : (3R)
HCl
90%98% de
HCl
i-PrOAc70 oC
OH
NH(R)
Ph
N
OOH
F
Ph
N(R)
Ph
OHO
F
3rd Generation Synthesis
Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747Agami, C.; Couty, F.; Prince, B.; Venier, O. Tetrahedron Lett 1993, 34, 7061-7062
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BF3 Et2O
F
(R)
O
N
O
Ph
DIBALH
F
(R)(S)
O
N
OH
Ph
toluene/THF-20oC
trans / cis8 / 1
CCl3CN
K2CO3
F
O
N
O
Ph
NH
CCl3
CF3
CF3
HO
F
O
N
O
Ph
CF3
CF31) H2, 5% Pd / C
TsOH H2O, toluene/EtOH
2) NCS, DMF, K2CO3, 0oC, 0.5hrs
3) DBU 85% (three steps)trans / cis
96 / 4
F
O
N
O
CF3
CF3
3rd Generation Synthesis: trans Acetalization
Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747
-Difficult to remove CCl3CN-Shifts back to SM
N
Nelson, T. D. Synthesis of Aprepitant. Strategies and Tactics in Organic Synthesis;Harmata, M., Ed.; Elsevier: San Diego; 2005: pp 321-351.
N
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3rd Generation Synthesis:cis Hydrogenation
Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747Cowden, C.J. et al. Tetrahedron Lett. 2000, 41, 8661-8664.
F
O
N
O
CF3
CF3
F
O
NH
O
CF3
CF3HN
HN N
ClO
K2CO3 / DMF N
F
O O
CF3
CF3
NNH
HN
OAprepitant98%
81% (four steps)>99% cis
H2
5% Pd / C
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Pros/Cons of 3rd Generation Synthesis
Pros:52% yield (longest linear sequence)Cheap, available starting materialsNo cryogenic temperatures
Cons:Removal of trichloroacetonitrileInversion of C3 stereocenterOperationally lengthy synthesis (12 steps)
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OutlineWhat is Process Chemistry?Drug Development Timeline and CostGeneral ConsiderationsEmend®
Discovery SynthesisRefined Process Chemistry Route3rd Generation SynthesisCommercial Synthesis
Conclusion
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Commercial ScaleRetrosynthetic Analysis
N
F
O O
CF3
CF3
NNH
HN
O
NH
F
O O
CF3
CF3
NNH
HN
OCl
N
O O
CF3
CF3
O
Ph
N
O O
O
Ph
O CF3
CF3
CF3
OH
3
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
Solve deprotonationproblem with adjacent sp2
center (C3)Dynamic Resolution
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Commercial Scale Synthesis
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
OH
NH
Ph
OHO
O
N
OCOOH
Ph
N
O
O
OH
Ph
76%
THF/H2O heat2.3 eq
OH
N
Ph
O
OH
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N
O
O
OH
Ph
O
O
O
CF3F3C
CH3CNN
O
O
O
Ph
OF3C
F3C CF3
(R)HO
CH3CN
0.5 eq BF3 Et2O1)
2) NaOH
N
(R)O
O
O
Ph
(R)
CF3
CF3
N
(S)O
O
O
Ph
(R)
CF3
CF3
55 : 45
Commercial Scale Synthesis Cont.
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
95% overall yield
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40
Equilibration Studies
N
(R)O
O
O
Ph
(R)
CF3
CF3
N
(S)O
O
O
Ph
(R)
CF3
CF3
65 : 35
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
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41
Crystallization-Induced Asymmetric Transformation
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135. Anderson, N. G. Org. Proc. Res. Dev. 2005, 9, 800-813.
N
O
O
O
Ph
CF3
CF3
55 : 45 R : S
1)Δ , -CH3CN +heptane
2) OH0.9 eq
3) -10 to -5 oC, seed with R diastereomer
4) O-K+0.3 eq
5 hours
N
(R)O
O
O
Ph
CF3
CF3
84% yield> 99% de
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CF3
CF3
OO
N O
Ph
Me
MgBr
F
CF3
CF3
OO
NH
Me
F
THF
91%>300 : 1
cis : trans
CF3
CF3
OO
N
Ph
Me
F
OMgBr
1) MeOH2) Pd/C, H2, 1.5eq TsOH
CF3
CF3
OO
N
Me
F
CF3
CF3
OO
NH
Me
F
TsOH
Nucleophilic Addition
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135. Brands, K. M. J. et al. Org. Proc. Res. Dev. 2006, 10, 109-117.
-Unacceptable levels of defluorinated product
CF3
CF3
OO
NH
Me
0.5%
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DefluorinationCF3
CF3
OO
Me
F
N
Pd*
CF3
CF3
OO
Me
Pd
N
F
CF3
CF3
OO
Me
H
N
H2
CF3
CF3
OO
NH
Me
F
H2
CF3
CF3
OO
NH
Me
H
Brands, K. M. J. et al. Org. Proc. Res. Dev. 2006, 10, 109-117.
Catalyst decreased to 3-6wt% Increase H2 pressure to 20psi Gas-liquid mass transfer rate increased Defluorinated product becomes <0.1%
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Final Step: Triazolinone
F
NH
O O
CF3
CF3 HN
NH
NO
Cl
K2CO3DMF / H2O
F
N
O O
CF3
CF3
HN
NH
NO
Aprepitant98%
Cowden, C. J. et al Tetrahedron Lett. 2000, 41, 8661.
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Presidential Green Chemistry Challenge Award - 2005
Convergent synthesisOverall yield 55% (6 steps)Uses 20% of raw materials as original synthesis Reduce waste by 85%
340,000L / metric ton aprepitant
http://www.epa.gov/greenchemistry/past.htmlC&E News June 27, 2005 pg 40-43
N
O OH
O
Ph
CF3
CF3
OH
HNNH
N
O
F
BrMg
CF3
CF3
O
N
O
F
HNNH
N
O
Cl
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OutlineWhat is Process Chemistry?Drug Development Timeline and CostGeneral ConsiderationsEmend®
Discovery SynthesisRefined Process Chemistry Route3rd Generation SynthesisCommercial Synthesis
Conclusions
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Emend® Process Research
10 years of process research
4 synthetic generations
Increased yield from 12% to 55%
Eliminated toxic chemicals
Reduced waste
Developed prior to drug launch
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Conclusion
Process chemistry is more than just scale-upSafe
Cost effective
Environmentally friendly
Timely development
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Acknowledgements
Prof. Stephen F. NelsenNelsen Group Members
Mike WeaverYun LuoGaoquan LiBrian Schuld
Kim Schultz
Practice Talk AttendeesKatie AlfareErik HadleyCaroline PharrWill PomerantzVicki Wilde
Soo Hyuk Choi
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Crystal Structure of CIAT product (slide 41)
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
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Crystal Structure of Aprepitant
O(R)
(S)
N
H
O
H
RF
(R)
CF3F3C
N(S)
(R)
O
HO R
F
(R)
F3C
F3C Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
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Modified Strecker Reaction (slide 15)
F
O
HNa2S2O5
H2OF
OH
NaO3SCN-
F
CN
HO
NH
OH
F
CN
N
OH1) HCl(g) H2O2) KHCO3
F
N
O O
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Trizolinone Ring Synthesis (Slide 26)
HN
NH2
H2N
O
OOO
Cl
HN
NH
NO
Cl
90%
H
12
HN
NH
H2N
O O
O Cl
H
HN
N
H2N
O
O
Cl
H
HN
N
H2N
O
Cl
OOO
Cl
H
Cl Cl Me OOO
Cl
HH
O
O
Cl
Decomposition:
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3rd Generation Synthesis of Oxazinone Mechanism (slide 32)
F
O
OOH
NH(R)
Ph
O
N(R)
Ph
OH
F
O
N(R)
Ph
O
F1
2
Agami, C.; Couty, F.; Prince, B.; Venier, O. Tetrahedron Lett 1993, 34, 7061-7062.
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Lactam Lactol Synthesis (slide38)OH
NH
Ph
HOO
OH N
Ph
OH2
OHOHO
N
Ph
OHOHO
N
O
Ph
NH
O
O
O
OH
OH
H
HNH
O
O
HO
H
N
O
O
OH
Ph
H