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Process Chemistry: From Millimole to KilomoleKevin P. SchultzNelsen GroupApril 6, 2006
2
OutlineWhat is Process Chemistry?
Drug Development Timeline and Cost
General Considerations
Emend®From Discovery to Scale-Up
Conclusion
3
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)
4
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.
5
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.
6
Total Drug Development Cost$400 - $800 million per approved drug
DeMasi, J. A. et al. J. Health Economics 2003, 22, 51–185.
7
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)
8
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
9
OutlineWhat is Process Chemistry?
Drug Development Timeline and Cost
General Considerations
Emend®From Discovery to Scale-Up
Conclusion
10
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
11
OutlineWhat is Process Chemistry?Drug Development Timeline and CostGeneral ConsiderationsEmend®
Discovery SynthesisRefined Process Chemistry Route2nd Generation SynthesisCommercial Synthesis
Conclusion
12
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
13
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.
14
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
15
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
16
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
17
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
18
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.
19
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
20
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.
21
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.
22
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
23
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.
24
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
25
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.
26
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.
27
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.
28
OutlineWhat is Process Chemistry?Drug Development Timeline and CostGeneral ConsiderationsEmend®
Discovery SynthesisRefined Process Chemistry Route3rd Generation SynthesisCommercial Synthesis
Conclusion
29
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.
30
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.
31
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
32
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
33
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
34
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
35
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)
36
OutlineWhat is Process Chemistry?Drug Development Timeline and CostGeneral ConsiderationsEmend®
Discovery SynthesisRefined Process Chemistry Route3rd Generation SynthesisCommercial Synthesis
Conclusion
37
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
38
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
39
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
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
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
42
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%
43
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%
44
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.
45
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
46
OutlineWhat is Process Chemistry?Drug Development Timeline and CostGeneral ConsiderationsEmend®
Discovery SynthesisRefined Process Chemistry Route3rd Generation SynthesisCommercial Synthesis
Conclusions
47
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
48
Conclusion
Process chemistry is more than just scale-upSafe
Cost effective
Environmentally friendly
Timely development
49
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
50
51
Crystal Structure of CIAT product (slide 41)
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
52
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
53
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
54
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:
55
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.
56
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
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