How Green was my How Green was my Process ?: Process ?: Case Studies of the Case Studies of the Role of Process Role of Process Chemistry in Drug Chemistry in Drug Development Development Steven A. Weissman (Ph.D. ’87) Steven A. Weissman (Ph.D. ’87) Tufts University Tufts University 29March 2004 29March 2004 “ “ Industrial Strength Chemistry” Industrial Strength Chemistry”
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How Green was my How Green was my Process ?:Process ?:
Case Studies of the Role of Case Studies of the Role of Process Chemistry in Drug Process Chemistry in Drug
DevelopmentDevelopmentSteven A. Weissman (Ph.D. ’87)Steven A. Weissman (Ph.D. ’87)
ClinicalClinical: 50-500 kg: Ph I-III human trials, long-term : 50-500 kg: Ph I-III human trials, long-term safetysafety
Post ClinicalPost Clinical: transfer process technology to : transfer process technology to Manufacturing (1000 kg - metric ton quantities/yr; Manufacturing (1000 kg - metric ton quantities/yr; depending on dose)depending on dose)
Advent of Process ResearchAdvent of Process Research
MSc Degree- Univ. LiverpoolMSc Degree- Univ. Liverpool
Dedicated ACS Journal (Dedicated ACS Journal (Org Process R&D)Org Process R&D)
Wall Street JournalWall Street Journal cover story cover story
What is Process Research ?What is Process Research ?
““The ideal chemical process is that The ideal chemical process is that which a one-armed operator can which a one-armed operator can perform by pouring the reactants perform by pouring the reactants
into a bath tub and collecting pure into a bath tub and collecting pure product from the drain hole”product from the drain hole”
Sir John Conforth Sir John Conforth
(1975 Nobel Prize: Chemistry)(1975 Nobel Prize: Chemistry)
What is Process Research ?What is Process Research ?
• Salt selection: based on stability, suitabilitySalt selection: based on stability, suitability• Solid State Properties: Solvent dependantSolid State Properties: Solvent dependant
12 Principles of Green Chemistry12 Principles of Green Chemistry
Developed in 1997 by:Developed in 1997 by:
Paul Anastas- EPAPaul Anastas- EPA
Prof John Warner- UMass-BostonProf John Warner- UMass-Boston
Presidential Green Chemistry Presidential Green Chemistry Challenge Challenge
12 Principles of Green Chemistry12 Principles of Green Chemistry
1.1. PreventionPrevention: It is better to prevent : It is better to prevent waste than to treat/clean up after waste than to treat/clean up after its created.its created.
12 Principles of Green Chemistry12 Principles of Green Chemistry
2. 2. Atom EconomyAtom Economy: : synthetic methods synthetic methods should be designed to incorporate all the should be designed to incorporate all the atoms used in the process into the final atoms used in the process into the final product product
% atom economy =% atom economy =
100 x 100 x MW of all atoms utilizedMW of all atoms utilized
MW of all reagents/reactants usedMW of all reagents/reactants used
Example of 100% efficiency: Rearrangements, Diels-Example of 100% efficiency: Rearrangements, Diels-AlderAlder
Atom Economy:ExampleAtom Economy:Example
Atom Economy = (MW of atoms utilized/MW of all reactants) X 100 = (137/275) X 100 = 50%
12 Principles of Green Chemistry12 Principles of Green Chemistry
Products should be designed to effect Products should be designed to effect their desired function while their desired function while minimizing toxicityminimizing toxicity
Example: Use of single enantiomer drug vs Example: Use of single enantiomer drug vs racemateracemate
12 Principles of Green Chemistry12 Principles of Green Chemistry
5. 5. Use Safer Solvents/AuxiliariesUse Safer Solvents/Auxiliaries
Use of innocuous solvents should be Use of innocuous solvents should be considered (e.g. water, supercritical considered (e.g. water, supercritical COCO22))
Avoid use of unnecessary substancesAvoid use of unnecessary substances
12 Principles of Green Chemistry12 Principles of Green Chemistry
6. 6. Design for Energy Efficiency:Design for Energy Efficiency:
Energy requirements for a process Energy requirements for a process should be recognized for should be recognized for environmental and economic impactenvironmental and economic impact
Avoid the use of protecting groups Avoid the use of protecting groups when possible as it add steps, requires when possible as it add steps, requires extra reagents and generates more extra reagents and generates more waste.waste.
12 Principles of Green Chemistry12 Principles of Green Chemistry
9. 9. Catalysis:Catalysis:
Use of catalytic reagents is far Use of catalytic reagents is far superior than stoichiometric amountssuperior than stoichiometric amounts
Example: using air as a source of oxygen for Example: using air as a source of oxygen for oxidation reactionoxidation reaction
12 Principles of Green Chemistry12 Principles of Green Chemistry
10. 10. Design for Degradation:Design for Degradation:
Ideally, process products and by-Ideally, process products and by-products should breakdown into products should breakdown into innocuous materials and/or do not innocuous materials and/or do not persist in the environmentpersist in the environment
12 Principles of Green Chemistry12 Principles of Green Chemistry
11.11.Real Time Analysis:Real Time Analysis: Analytical methods designed for Analytical methods designed for
‘real-time’‘real-time’ In-process monitoring/control of a In-process monitoring/control of a
reactionreaction
Example: Example: Reactor-IRReactor-IR (in-situ probe for (in-situ probe for monitoring reactions)monitoring reactions)
13 Principles of Green Chemistry13 Principles of Green Chemistry
Process EconomicsProcess Economics- Minimize - Minimize inventory cost of API via:inventory cost of API via:
Clinical Trials: halted in 1993 due to anemia side-effects
Original Bromination
OMe
Br
O
OMe
OH
OMe O
OMe
OH Br2 dioxane
OMe
Br
O
OMe
OH
OMe
Br
O
OH
OHBr
84% yield
93% purity
5% 2%
Drawbacks: Use of toxic oxidant (bromine)
Use of suspect carcinogen (dioxane)
Product requires additional purification
Improved Bromination
OMe
Br
O
OMe
OH
OMe O
OMe
OH
94% yield
98% purity
water/NaOH
N
N
O
OBr
Br(0.55 equiv)
Green Chemistry Principles: Safer Solvents
Less Hazardous Chemical Synthesis
Other ExamplesOMe
Br
O
OMe
OH
90% yield
Br
OMe
O
OMe
OH
90 % yield
O
Br
OHO
O
86% yield
OMe
O
OH
MeO
MeO
Br
91 % yield
O
OMe
OHBr
98 % yield
O
OH
NR
Literature: 4 steps-17% yield
Auerbach, Weissman Tet Letters 1993, 931
Useful Methodology
Br
OMe
O
OMe
OH
N
O
O
OMe
MeO
Alkaloid Chelerythrine
Harayama et al Synthesis 2001, 444
OMe
MeO
N
O
O
O
J. Fuchs, R. Funk Org. Letters 2001, 3923
Alkaloid Lennoxamine
Case Study 2: Crixivan®
HIV Protease Inhibitor-AIDS therapyFDA Approval - March 1996
Fastest FDA Approval Ever (42 Days)Daily Dosage: 2400 mg
NNH OH
O
OHN
t-BuHN O
N . H2SO4N
NH OH
O
OHN
t-BuHN O
N . H2SO4
Retrosynthetic Analysis of Crixivan-I
5
2
Aminoindanol Amide
Glycidyl Fragment
Piperazine
++
41
3
Crixivan
" "(-)
NNH OH
O
OHN
HN O
N
N
OHN
N
NHY
OH N O
O
X
Retrosynthetic Analysis of Crixivan-II
5
2
41
3
NNH OH
O
OHN
t-BuHN O
N
Crixivan
* Five Asymmetric Centers (Arrows)
3-Picolyl Chloride
N
Cl
BocN
NH
t-BuHN O
H2N OH
O
ON
O 12
345+
Piperazine FragmentEpoxide Fragment
ON
O
Allyl Bromide
Br
(-)-cis-Aminoindanol
Synthesis of Pyrazine Carboxamide
CONHt-Bu
N
N
Original Route
CO2H
N
N C(O)Cl
N
N
(COCl)2 t-BuNH2
95% yield
Drawbacks:1. Use of costly Oxalyl Chloride2. CO and CO2 by-products3. Lengthy time cycle due to exothermic amination reaction4. Need for 3 equiv of volatile t-butylamine5. Filtration/Disposal of voluminous amine hydrochloride salt
Improved Route to Pyrazine Carboxamide
N
N
CN CONHt-Bu
N
N
t-BuOH, H2SO4
91 %
Ritter Reaction
Aq AcOH
5 oC/2 h
Green Chemistry Principles: - Prevention- Safer Solvents- Less Hazardous Chemical Synthesis- Energy Efficiency
Atom Economy Comparison
N
N
CO2H N
N
NH
O
N
N
CN
C5H4N2O2Mol. Wt.: 124.10
C5H3N3Mol. Wt.: 105.10
C9H13N3OMol. Wt.: 179.22
(COCl)2 [127]
2 t-butylNH2 [ 73]
H2SO4 [98]
t-BuOH [74]
H2O [18]
A
B
A: 179/[124+127+73+73] = 45 %
B: 179/[105 + 98 +74 +18] = 61%
Chiral Piperazine via Resolution/Racemization
Green Chemistry Principles: Prevention (Recycle R-isomer)Prevention (Recovery of PGA)Atom EconomyRenewable Feedstock (PGA)Catalysis
Green Chem Principles: Energy Efficient, Safer Solvent,
Reduced Derivitization, Prevention (SiO2 waste)
L778,123: Summary
N
N
O
Cl
N
N
CN
N
N
CN
Cl
HN
N
O
Cl
L778,123
DIEA/MeCN
83%
Br
CN
NH2
Cl
2 steps4 steps
+
Case Study #4: Synthesis of Emend
N
O
F
O
Me
N
HNNH
O
CF3
CF3
Emend®
Neurokinin-1 Receptor Antagonist
(Agonist is Substance-P)
• emesis (CINV)- FDA approved 2003• depression- Phase III trials -discontinued• asthma• arthritis• migraine• pain
Potential Indications:
synthesis/biology: Hale et. al. JMC 1998, 4607
Disconnection
N
O
F
O
Me
NHN
NH
O
CF3
CF3
NH
O
F
O
CF3
CF3
NH
O
F
O
Me
CF3
CF3
Diastereoselective Reduction
+ Me-epimer
1) H2, Pd/Al2O3 acetone
pTSA
2) pTSA
88% isolated yield (d.e. > 99%)
NBn
O
F
O
CF3
CF3
NH2
O
F
O
Me
CF3
CF3
Med Chem Route to Vinyl EtherCHO
F
HN
HO
Ph
N
O
Ph F
O
+1) NaCN 2) HCl
3) KHCO3
88%
BCSA
N
O
F
O
H
Ph
89% isolated yield
e.e. > 98%
IpAc(-)-BCSA
1) L-selectride
2)
CF3F3C
C(O)Cl
NBn
O
F
O
CF3
CF3O
Drawbacks: (1) use of toxic NaCN; (2) costly resolving agent;(3) Lack of racemization/recycle
Petasis Methylenation
+
80 oC
92% isolated yield
toluene
Cp2TiMe2
(Cp2TiMe)2O
Cp2TiCl2
Cp2TiCl2
2.5 eq.
NBn
O
F
O
CF3
CF3
NBn
O
F
O
CF3
CF3O
Drawbacks: Titanocene reagent is very expensive and potentially hazardous------recycling imperative-- HUGE capital investment
Vinyl Ether via Hofmann Elimination ?
NBn
O
F
O
CF3
CF3
N
OO
Ar-FBn
(F3C)2-Ar
X
N
O
F
OH
CF3F3C
HO
NH
OH
CF3F3C
HO
? ?
?
Synthesis of Aminodiol
CF3F3C
Sharpless AD
CF3F3C
HOOH
80% yield
92% ee: (S)-isomer 99% ee upgrade
1.Ms-Cl/lutidine
2. ethanolamineCF3F3C
HONH
OH
60%
Morpholine Synthesis
NBn
O
F
O
CF3
CF3
N
OO
Ar-FBn
(F3C)2-Ar
X
N
O
F
OH
CF3F3C
HO
NH
OH
CF3F3C
HO
Morpholine via Novel Condensation ?
CF3F3C
HONH
OH
HO
HO
CF3F3C
HON
O OH
F
B(OH)2
CF3F3C
HON
O OH
Ar-F
86% yield
Petasis et. al. JACS 1997, 119, 445.
Synthesis of Bicyclic Acetal
N
O
Ar-F
OH
(F3C)2-Ar
HO
13:87
EtOAc/77 oC N
O
Ar-F
OH
(F3C)2-Ar
HO
98% yield
N
O
Ar-F
OH
(F3C)2-Ar
HO
HCl (g)
MCH
H
Cl
N
OO
Ar-F
(F3C)2-Ar
1. aq base/EtOAc
2. TBP/DIAD/THF
86% yield
Regioselective ‘Hofmann’ Elimination
N
O
O
BnAr-F
(F3C)2 Ar
IN
O
F
O
CF3
CF3
Bn
aq EtOH
1 equiv NaOH
5 h/40-75 oC
90% yield
99% ee
H
N
OO
Ar-F
(F3C)2-Ar
BnIacetone
89% yield
H
more acidic proton
N
O
Ar-F
O
Bn
(F3C)2 Ar
X
Summary
CF3F3CCF3F3C
HONH
OH
N
O
Ar-F
OH
(F3C)2-Ar
HO
N
O
F
O
CF3
CF3
Bn
7 steps overall
Green Chemistry Principles:Prevention (no Ti waste)Less Hazardous Chemical Synthesis (CN, DMT)Catalysis (Sharpless, Hydrog)Atom Economy More Economic (avoid BCSA)
Pye et. al. Chem Eur J. 2002, 8, 1372
Unlocking the Potential of Unlocking the Potential of Process InnovationProcess Innovation
EPA)EPA) Downward Pricing PressureDownward Pricing Pressure Greater Competition in treatment Greater Competition in treatment
optionsoptions More complex moleculesMore complex molecules Corporate consolidationCorporate consolidation Dwindling # of diseases to conquerDwindling # of diseases to conquer
Lessons LearnedLessons Learned
Process Development as a Process Development as a Competitive Weapon/Leveraging Competitive Weapon/Leveraging
CapabilitiesCapabilities
““The power of process development lies The power of process development lies in how it helps companies achieve in how it helps companies achieve accelerated time to market, rapid accelerated time to market, rapid
production ramp-up and a stronger production ramp-up and a stronger proprietary position”proprietary position”
Lessons LearnedLessons Learned
““A firm that can develop A firm that can develop sophisticated process sophisticated process
technologies more rapidly and technologies more rapidly and with fewer development with fewer development
resources has strategic options resources has strategic options that less capable competitors that less capable competitors
lacklack””
Further ReadingFurther Reading Practical Process Research & Development; Practical Process Research & Development;
Neal AndersonNeal Anderson
The Merck Druggernaut: The Inside Story of a The Merck Druggernaut: The Inside Story of a Pharmaceutical GiantPharmaceutical Giant; ; Fran HawthorneFran Hawthorne
The Development Factory: Unlocking the Potential of The Development Factory: Unlocking the Potential of Process InnovationProcess Innovation; ; Gary P. Gary P. PisanoPisano
Principles of Process Research and Chemical Development Principles of Process Research and Chemical Development in the Pharmaceutical Industryin the Pharmaceutical Industry; ; Oljan RepicOljan Repic
Process Chemistry in the Pharmaceutical Industry; Process Chemistry in the Pharmaceutical Industry; Kumar Kumar GadamasettiGadamasetti