Transcript Process Chemistry: From Milimole to Kilimole

Process Chemistry:
From Millimole to
Kilomole
Kevin P. Schultz
Nelsen Group
April 6, 2006
Outline

What is Process Chemistry?

Drug Development Timeline and Cost

General Considerations

Emend®
 From

Discovery to Scale-Up
Conclusion
2
What is Process Chemistry?


Safe
Environmentally
friendly
Efficient
Economical
($ and atom)


HO
CO2
HN
HCl
Cl
HO
O
CF3
O
N
N
F
CF3
H
N
N
F
O
N
H
N
Cl
Cl
Zoloft®
Pfizer
O
O
Claritin®
Schering-Plough
HN
N
Emend®
Merck
O
Lipitor®
Pfizer
3
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.
4
Drug Development Timeline

Target
Screen(s) Hit
Average of 12-15 yrs
Lead
Candidate
Launch
Patent
Expiration
CLINICAL
P
A
T
E
N
T
D I S C O V E R Y
SAFETY/PHARMACEUTICAL STUDIES
P R O C E S S
4.5 yrs
200-300 gms
2 yrs
R E S E A R C H
8.2 years
< 100 kg
Gadamasetti, Kumar G. Process Chemistry in the Pharmaceutical
Industry. Marcel Dekker, Inc. New York: 1999.
100-2000 kg
5
Total Drug Development Cost

$400 - $800 million per approved drug
DeMasi, J. A. et al. J. Health Economics 2003, 22, 51–185.
6
Need For Efficient Process Chemistry

Patent protection for
20 years

Generic drug application:
Abbreviated New Drug
Application (ANDA)
http://www.fda.gov/cder/index.html
7
Presidential Green Chemistry
Challenge Award


Established in 1995 by the EPA
For innovations in cleaner, cheaper and smarter
chemistry
HN
O
HCl
N
HN
O
H2N
CF3
O
N
N
N
O
Cl
HO
F
O
Cl
Cytovene®
2000 Roche Corp.
Reduced liquid waste:
1120 metric tons / year
Reduced solid waste:
25 metric tons / year
CF3
H
N
OH
Zoloft®
2002 Pfizer, Inc.
Reduced waste:
HCl (conc): 150 metric tons / year
TiO2: 440 metric tons / year
HN
N
Emend®
2005 Merck
Reduced waste:
340,000 L / metric ton
www.epa.gov/greenchemistry/presgcc.html
http://pubs.acs.org/cen/coverstory/8026/8026greenchemistry.html
8
Outline

What is Process Chemistry?

Drug Development Timeline and Cost

General Considerations

Emend®
 From

Discovery to Scale-Up
Conclusion
9
General Considerations for Process Chemistry

Avoid column chromatography

Seeding helps crystallization

Avoid desiccants, use azeotrope

Avoid solvents with flash point < 15 ºC

Ether, hexanes, DCM

Temperature range -40 to 120 ºC

Avoid protecting groups

Impurities of > 0.1% must be analyzed
10
Outline




What is Process Chemistry?
Drug Development Timeline and Cost
General Considerations
Emend®
 Discovery
Synthesis
 Refined Process Chemistry Route
 2nd Generation Synthesis
 Commercial Synthesis

Conclusion
11
O 2
Emend® - Aprepitant
CF3
O
N 3
N
CF3
F
HN
NH
O

hNK1 receptor antagonist (IC50 = 0.09 nM)1

Treatment of chemotherapy-induced emesis2

FDA approval in 2003

2005 Presidential Green Chemistry Challenge
Award3

1
3
Entered preclinical trials in 19931
Hale, J. J. et al; J. Med. Chem. 1998, 41, 4607-4614.
http://www.epa.gov/greenchemistry/past.html
2
Rupniak, N. M. et al; Eur. J. Pharmacol. 1997, 326, 201-209.
12
Discovery Synthesis Route
CF3
CF3
Me
Me
CF3
O
Me
CF3
O
O
N
CF3
O
O
N
H
H
N
F
H2N
O
N
O
N
F
O
HN
CF3
F
Ph
Cl
N
O
N
H
CF3
CF3
O
O
H2C
CF3
O
O
O
O
CF3
O
N
N
Ph
N
F
Ph
F
Hale, J. J. et al; J. Med. Chem. 1998, 41, 4607-4614.
Ph
F
13
Discovery Synthesis:
Oxazinone
HO
O
O
O
O
1) KHMDS
N
O
O
N
NH
2)
O
Ph
F
S
Ph
O
O
Ph
N3
O
F
83%
N3
O
67%
92% de
F
1) LiOH
2) HCl
3) H2, Pd/C
Br
O
1) Br
O
HO
O
PhCHO
NaOH
NaBH4
(i-Pr)2NEt
DMF
HN
N
Ph
F
74% (two steps)
92% ee

O
H2N
2) HCl
Ph
HO
F
F
40% overall yield
Hale, 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
14
One-Pot Synthesis of Oxazinone
1) Na2S2O5,
NaCN
H2O, MeOH
O
HO
NH
HCl(g)
H
HCl
N
OH
2)
O
CN
F
N
Ph
NH
F
Ph
F
in i-PrOAc
1.2 eq H2O
Ph
O
O
O
O
HCl
KHCO3
N
N
Ph
F
racemate
80% yield
Ph
F
> 1.2 eq H2O
HO
HO
- Washed aminonitrile with 15 wt % NaCl
O
N
Ph
Nelson, T. D.; Bhupathy, M. European Patent 1112259, 2001.
F
15
Dynamic Resolution
SO3H
O
Br
O
O
O
1.2 eq O
(S)
(S)
(-) - BCSA
N
BCSA
O
NH3
toluene
(S)
N
N
i-PrOAc, reflux
Ph
F
Ph
F
99% de
90% yield
O
O
i-PrOAc, HCl
(R)
O
BSCA
Ph
F
NH4
N
Ph
F
Alabaster, R. J.; Gibson, A. W.; Johnson, S. A.; Edwards, J. S.;
Cottrell, I. F. Tetrahedron: Asymmetry 1997, 8, 447-450
16
Discovery Synthesis Route
CF3
CF3
Me
Me
CF3
O
Me
CF3
O
O
N
CF3
O
O
N
H
H
N
F
H2N
O
N
O
N
F
O
HN
CF3
F
Ph
Cl
N
O
N
H
CF3
CF3
O
O
H2C
CF3
O
O
O
O
CF3
O
N
N
Ph
N
F
Ph
F
Ph
F
17
Acyl Acetal Formation
O
O
O
CF3
N
L-Selectride
THF/toluene
> -60 oC
CF3
CF3
O
Ph
F
O
(S)
Cl
(S)
CF3
N
O
O
O
H
O
O
Ph
F
(S)
N
N
CF3
Ph
F
Ph
CF3
> -60 oC
L-Selectride
THF/toluene
< -60 oC
strict cryogenic
temperatures
F
O
O
CF3
Cl
O
CF3
O
O
(S)
N
N
< -60 oC
Ph
F
O
(R)
Ph
F
99% de
82% yield
Ashwood, M. S.; Cottrell, I. F.; Davies, A. J. Tetrahedron: Asymmetry 1997, 8, 957.
18
Discovery Synthesis Route
CF3
CF3
Me
Me
CF3
O
Me
CF3
O
O
N
CF3
O
O
N
H
H
N
F
H2N
O
N
O
N
F
O
HN
CF3
F
Ph
Cl
N
O
N
H
CF3
CF3
O
O
H2C
CF3
O
O
O
O
CF3
O
N
N
Ph
N
F
Ph
F
Ph
F
19
Petasis Reagent
Me
Petasis Reagent
Ti
Me
Cl
MeMgCl
Cl
o
Ti
Me
heat
Ti
-5 to -10 C
Me
-CH4
decomposes in
solid state
energetic
decomposition
CH2
Ti
titanium carbene
reactive and unstable
O
excess
Ti
undesired
products
CH2
R'
R
CH2
O
R'
R
O
Cp
Cp
Ti
O
excess
Me
Ti
Me
R'
O
Ti
R
O
HCl
O
Ti
Ti
>2 eq of Petasis reagent necessary
recycle
Cl
Ti
Cl
major byproduct
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.
20
Sacrificial Ester
O
O
O
CF3
O
(R)
<
Ph
(S)
O
N
CF3
Ph
F
CF3
Me
CF3
CF3
Ti
Me
Ti
Cp
O
CF3
O
H2C
Cp
O
80 oC
O
O
THF/
toluene
(R)
(S)
(S)
O
N
(S)
N
Ph
F
O
(R)
(R)
N
Ph
O
CF3
CF3
Ph
F
O
O
0.75 eq
F
92%
Ti
Ph
Ti
O
Payack, J. F. et al Org. Proc. Res. Develop. 2004, 8, 256.
21
Discovery Synthesis Route
CF3
CF3
Me
Me
CF3
O
Me
CF3
O
O
N
CF3
O
O
N
H
H
N
F
H2N
O
N
O
N
F
O
HN
CF3
F
Ph
Cl
N
O
N
H
CF3
CF3
O
O
H2C
CF3
O
O
O
O
CF3
O
N
N
Ph
N
F
Ph
F
Ph
F
22
Hydrogenation
CF3
H2C
O
CF3
CF3
Me
Pd/Al2O3,
H2
O
O
Ph
O
CF3
(S)
O
+
(R)
EtOH:EtOAc
O
1:1
N
Me
CF3
(R)
(R)
(S)
CF3
O
(R)
(S)
(S)
N
N
F
Ph
F
Ph
91
:
F
9
Pd/Al2O3,
TsOH, H2
CF3
CF3
CF3
Me
O
O
O
(R)
N
86% yield
99%
de
F
O
(R)
TsOH
(S)
Me
CF3
(R)
CF3
CF3
(S)
O
TsOH
O
(R)
(S)
TsOH
(S)
N
H
N
H
F
Nelson, T. D. Synthesis of Aprepitant. Strategies and Tactics in Organic Synthesis;
Harmata, M., Ed.; Elsevier: San Diego; 2005: pp 321-351.
F
23
Discovery Synthesis Route
CF3
CF3
Me
Me
CF3
O
Me
CF3
O
O
N
CF3
O
O
N
H
H
N
F
H2N
O
N
O
N
F
O
HN
CF3
F
Ph
Cl
N
O
N
H
CF3
CF3
O
O
H2C
CF3
O
O
O
O
CF3
O
N
N
Ph
N
F
Ph
F
Ph
F
24
Triazolinone Ring
CF3
CF3
Cl
CF3
H2N
O
Me
Me
CF3
(R)
O
N
O
CF3
(R)
N
H
O
O
K2CO3, toluene,
DMSO
(S)
N
H
CF3
(R)
O
xylenes
140oC
(R)
(R)
Me
(S)
O
O
(R)
(S)
N
N
H2 N
O
F
N
O
H
N
F
N
H
F
O
HN
N
aprepitant
85%
- Charcoal treatment
- A single SN2 displacement was envisioned
Hale, J. J. et al; J. Med. Chem. 1998, 41, 4607-4614.
25
Facile Addition of Triazolinone Ring
H2N
O
H
N
O
O
Cl
O
NH2
O
H
N
MeOH, 20oC
N
H
3 days
HCl
Cl
N
90%
commercially
available
CF3
CF3
H
N
CF3
(R)
O
N
H
O
N
O
(S)
N
K2CO3, DMF,
1hr, RT
N
H
H
N
F
O
F
3
(R)
(R)
(S)
CF
(R)
O
Me
O
Me
Cl
HN
N
aprepitant
98%
Cowden, C. J. et al Tetrahedron Lett. 2000, 41, 8661.
26
1st Generation Synthesis: 1993-1999


43% overall yield
(longest linear
sequence)
Clinical trials



Larger doses necessary
Good results for
antiemesis
Possible antidepressant

Key improvement areas

Chiral Acid – BCSA



L-Selectride



Expensive (1kg NH4
salt= $4500)
Unreacted acid lost
Expensive
Strict cryogenic
temperatures
Dimethyl titanocene


Expensive
Toxic
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.
27
Outline




What is Process Chemistry?
Drug Development Timeline and Cost
General Considerations
Emend®
 Discovery
Synthesis
 Refined Process Chemistry Route
 3rd Generation Synthesis
 Commercial Synthesis

Conclusion
28
Logical 3rd Generation Retrosynthesis
CF3
CF3
CF3
CF3
CF3
O
O
CF3
O
O
OH
N
N
H
N
P
F
H
N
O
N
H
O
LG
F
N
Cl
O
N
H
N
Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747.
N
P
F
29
Cis Acetalization Approach
O
OH
O
F3 C
N
N
O
Ph
Me
DIBALH
F
OH
N
Ph
CF3
F
Ph
O
Lewis Acid
CF3
F
O
OR
1) base
CF3
N
O
2) RCl
Ph
O
F
R= C(O)CH3
C(O)CF3
C(NH)CCl3
N
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.
30
3rd Generation Retrosynthesis
CF3
CF3
Cl
CF3
O
CF3
H
N
O
CF3
O
CF3
O
O
O
N
H
N
H
N
O
N
N
H
N
F
F
O
F
N
N
H
O
NH
OH
CF3
O
O
O
OH
O
CCl3
F
N
OH
Ph
N
H
Ph
N
F
Ph
Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747
CF3
F
OH
31
3rd Generation Synthesis
OH
O
O
O
O
O
AcOH /
N
i-PrOAc
(R)
(R)
F
Ph
Ph
F
i-PrOAc
70 oC
HCl
(R)
HCl
NH
O
N
(R)
Ph
F
90%
98% de
2:1
(3S) : (3R)
F
F
OH
HO
O
O
N
N
(R)
Ph
Ph
Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747
Agami, C.; Couty, F.; Prince, B.; Venier, O. Tetrahedron Lett 1993, 34, 7061-7062
32
3rd Generation Synthesis:
trans Acetalization
O
O
NH
O
DIBALH
(R)
N
F
N
K2CO3
Ph
F
-Difficult to remove CCl3CN
-Shifts back to SM
O
O
N
CF3
F
O
1) H2, 5% Pd / C
TsOH H2O, toluene/EtOH
2) NCS, DMF, K2CO3,
0oC, 0.5hrs
3) DBU
N
N
O
CCl3
N
Ph
trans / cis
8/1
CF3
O
CCl3CN
(R)
toluene/THF
-20oC
Ph
OH
(S)
F
BF3 Et2O
CF3
HO
CF3
O
CF3
N
CF3
Ph
F
85% (three steps)
trans / cis
96 / 4
Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747
Nelson, T. D. Synthesis of Aprepitant. Strategies and Tactics in Organic Synthesis;
Harmata, M., Ed.; Elsevier: San Diego; 2005: pp 321-351.
33
3rd Generation Synthesis:
cis Hydrogenation
CF3
O
CF3
O
O
CF3
O
CF3
F
O
HN
5% Pd / C
N
H
CF3
O
H2
N
Cl
H
N
CF3
N
N
K2CO3 / DMF
H
N
F
81% (four steps)
>99% cis
O
F
O
Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747
Cowden, C.J. et al. Tetrahedron Lett. 2000, 41, 8661-8664.
N
H
N
Aprepitant
98%
34
Pros/Cons of
3rd Generation Synthesis
Pros:



52% yield (longest linear
sequence)
Cheap, available starting
materials
No cryogenic
temperatures
Cons:



Removal of
trichloroacetonitrile
Inversion of C3
stereocenter
Operationally lengthy
synthesis (12 steps)
35
Outline




What is Process Chemistry?
Drug Development Timeline and Cost
General Considerations
Emend®
 Discovery
Synthesis
 Refined Process Chemistry Route
 3rd Generation Synthesis
 Commercial Synthesis

Conclusion
36
Commercial Scale
Retrosynthetic Analysis
CF3
CF3
CF3
CF3
CF3
O
O
O
N
H
N
H
N


O
O
N
O
F
F
O
N
H
CF3
O
Ph
H
N
N
Cl
O
Solve deprotonation
problem with adjacent sp2
center (C3)
Dynamic Resolution
N
H
N
O
CF3
CF3
O
O
3
N
O
Ph
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
CF3
OH
37
Commercial Scale Synthesis
OH
O
2.3 eq
NH
O
O
THF/H2O
COOH
heat
N
OH
Ph
Ph
O
OH
N
O
Ph
76%
OH
O
N
OH
Ph
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
38
Commercial Scale Synthesis Cont.
O
O
OH
F3C
O
O
CF3
O
HO
(R)
O
1) 0.5 eq BF3 Et2O
CH3CN
O
N
F3C
O
N
CH3CN
O
F3C
Ph
2) NaOH
Ph
CF3
CF3
CF3
(R)
O
(R)
O
O
(R)
N
CF3
O
CF3
95% overall yield
(S)
O
N
Ph
O
Ph
55
:
45
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
39
Equilibration Studies
CF3
(R)
O
CF3
CF3
(R)
O
O
(R)
N
O
(S)
O
N
Ph
65
CF3
:
Ph
O
35
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
40
Crystallization-Induced
Asymmetric Transformation
CF3
CF3
1)  , -CH3CN +heptane
OH
2) 0.9 eq
CF3
CF3
O
O
O
o
3) -10 to -5 C,
seed with R diastereomer
N
(R)
N
O
Ph
4) 0.3 eq
55 : 45
R:S
O
O-K+
O
Ph
84% yield
> 99% de
5 hours
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.
41
Nucleophilic Addition
CF3
CF3
CF3
MgBr
Me
Me
CF3
Me
O
OMgBr
F
O
Ph
0.5%
Ph
CF3
CF3
Me
O
TsOH
N
H
F
Me
Me
CF3
F
1) MeOH
2) Pd/C, H2,
1.5eq TsOH
-Unacceptable levels of
defluorinated product
CF3
O
N
O
N
N
H
O
O
O
O
CF3
CF3
THF
CF3
CF3
91%
>300 : 1
cis : trans
O
O
O
O
N
N
H
F
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.
F
42
Defluorination
CF3
Me
CF3
O
CF3
CF3
Me
Me
Pd*
O
O
N
O
O
O
N
N
F
CF3
CF3
H
Pd F
H2
H2

CF3

Me
CF3
O

O

N
H
Catalyst decreased to 3-6wt%
Increase H2 pressure to 20psi
Gas-liquid mass transfer rate
increased
Defluorinated product becomes
<0.1%
F
CF3
Me
CF3
O
O
N
H
H
Brands, K. M. J. et al. Org. Proc. Res. Dev. 2006, 10, 109-117.
43
Final Step: Triazolinone
CF3
CF3
Cl
CF3
O
O
O
N
H
N
H
CF3
H
N
K2CO3
DMF / H2O
O
O
N
N
H
N
F
O
N
H
Cowden, C. J. et al Tetrahedron Lett. 2000, 41, 8661.
F
N
Aprepitant
98%
44
Presidential Green Chemistry
Challenge Award - 2005

Convergent synthesis
O
OH
N
O
CF3
Ph
OH
N
 Overall
yield 55% (6 steps)
 Uses
20% of raw materials as
original synthesis
 Reduce waste by 85%
CF3
Cl
HN
BrMg
NH
F
O
CF3
CF3

340,000L / metric ton aprepitant
O
O
N
N
F
HN
NH
O
http://www.epa.gov/greenchemistry/past.html
C&E News June 27, 2005 pg 40-43
45
Outline




What is Process Chemistry?
Drug Development Timeline and Cost
General Considerations
Emend®
 Discovery
Synthesis
 Refined Process Chemistry Route
 3rd Generation Synthesis
 Commercial Synthesis

Conclusions
46
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
47
Conclusion

Process chemistry is more than just scale-up
 Safe
 Cost
effective
 Environmentally
 Timely
friendly
development
48
Acknowledgements


Prof. Stephen F. Nelsen
Nelsen Group Members





Mike Weaver
Yun Luo
Gaoquan Li
Brian Schuld
Kim Schultz

Practice Talk Attendees

Katie Alfare
Erik Hadley
Caroline Pharr
Will Pomerantz
Vicki Wilde

Soo Hyuk Choi




49
50
Crystal Structure of CIAT product
(slide 41)
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
51
Crystal Structure of Aprepitant
F3C
CF3
(R)
O
O
F
N
(R)
R
(S)
H
H
F
F3C
O
O
(R)
F3 C
(S)
N
(R)
R
H
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
52
Modified Strecker Reaction
(slide 15)
O
OH
CN
Na2S2O5
H
H2O
CNNaO3S
HO
F
F
F
OH
NH
O
O
1) HCl(g)
H 2O
2) KHCO3
N
OH
CN
N
F
F
53
Trizolinone Ring Synthesis
(Slide 26)
H 2N
H
O
H
N
O
O
H2 N
NH2
O
1
2
N
H
O
Cl
Cl
O
H
N
H2N
O
H
N
H
N
Cl
O
O
H
H
N
Cl
H2 N
O
N
H
Cl
H
N
N
N
O
90%
Decomposition:
H
H
O
O
O
Cl
Cl
Me
H
O
O
O
O
Cl
O
Cl
Cl
54
3rd Generation Synthesis of
Oxazinone Mechanism (slide 32)
2
F
OH
O
OH
O
N
NH
F
(R)
Ph
O
O
1
N
(R)
Ph
O
(R)
Ph
Agami, C.; Couty, F.; Prince, B.; Venier, O. Tetrahedron Lett 1993, 34, 7061-7062.
F
55
Lactam Lactol Synthesis (slide38)
OH
NH
HO
HO
H
HO
O
O
N
HO
OH2
O
Ph
HO
H
O
N
Ph
O
O
N
OH
Ph
Ph
H
O
H
O
OH
N
O
O
O
OH
Ph
N
H
O
N
H
O
H
56
H