Upload
saweissman
View
9.841
Download
7
Tags:
Embed Size (px)
DESCRIPTION
Green Chemistry talk presented at Tufts University
Citation preview
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)
Tufts UniversityTufts University29March 200429March 2004
““Industrial Strength Chemistry”Industrial Strength Chemistry”
OverviewOverview
1.1. What is Process Research ?What is Process Research ?
2.2. 12 Principles of 12 Principles of Green ChemistryGreen Chemistry
3.3. Case Studies-Merck Process Case Studies-Merck Process ResearchResearch
4.4. Lesson Learned: “Unlocking the Lesson Learned: “Unlocking the Potential of Process Innovation” Potential of Process Innovation”
5.5. Q & AQ & A
Net Cost: $802 Million
Invested Over 15 Years Net Cost: $802 Million
Invested Over 15 Years
5,000–10,000Screened
250Enter Preclinical
Testing
5Enter
Clinical Testing
1
Compound Success Rates by Stage
Compound Success Rates by Stage
1616
1414
1212
1010
88
66
44
22
00
Phase II100–300 Patient Volunteers Used to Look for Efficacy and Side Effects
Phase II100–300 Patient Volunteers Used to Look for Efficacy and Side EffectsPhase III
1,000–5,000 Patient Volunteers Used to Monitor
Adverse Reactions to Long-Term Use
Phase III1,000–5,000 Patient
Volunteers Used to Monitor Adverse Reactions to
Long-Term Use FDA Review ApprovalFDA Review Approval
Additional Post-Marketing Testing
Additional Post-Marketing Testing
Phase I 20–80 Healthy Volunteers Used to Determine Safety
and Dosage
Phase I 20–80 Healthy Volunteers Used to Determine Safety
and Dosage
Preclinical TestingLaboratory and Animal Testing
Preclinical TestingLaboratory and Animal Testing
Discovery(2–10 Years)
Discovery(2–10 Years)
YearsYears
New Product Development – New Product Development – A Risky and Expensive PropositionA Risky and Expensive Proposition
New Product Development – New Product Development – A Risky and Expensive PropositionA Risky and Expensive Proposition
Source: Tufts Center for the Study of Drug DevelopmentSource: Tufts Center for the Study of Drug Development
Approved by the FDA
Approved by the FDA
What is Process Research ?What is Process Research ?MissionMission: :
To design elegant, practical, efficient, environmentally benign To design elegant, practical, efficient, environmentally benign
and economically viable chemical syntheses for Merck drug and economically viable chemical syntheses for Merck drug
substances (“active pharmaceutical ingredient” (API))substances (“active pharmaceutical ingredient” (API)) Pre-Clinical:Pre-Clinical: 50 g - 5 kg: Safety Assessment, 50 g - 5 kg: Safety Assessment,
formulation, metabolismformulation, metabolism
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)
Dedicated Conferences (ACS, Gordon)Dedicated Conferences (ACS, Gordon)
Books/CoursesBooks/Courses
C&E NewsC&E News cover stories cover stories
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 ?
An amalgam of:An amalgam of:
1.1. Modern synthetic organic methodologyModern synthetic organic methodology2.2. Physicochemical propertiesPhysicochemical properties
• Salt selection: based on stability, suitabilitySalt selection: based on stability, suitability• Solid State Properties: Solvent dependantSolid State Properties: Solvent dependant
Crystal Morphology: internal shape-affects solubility, Crystal Morphology: internal shape-affects solubility, stabilitystability
Crystal Habit: external shape-affects flowability, Crystal Habit: external shape-affects flowability, mixability mixability
Particle Size: can affect bioavailabilityParticle Size: can affect bioavailability
3.3. Purification/Isolation technologiesPurification/Isolation technologies
What is Process Research ?What is Process Research ?
4.4. Chemical Engineering principles: Chemical Engineering principles: mixing, heat transfer, vessel mixing, heat transfer, vessel configurationconfiguration
5.5. Practical Process Aspects:Practical Process Aspects:• SafetySafety• QualityQuality• CostCost• ReproducibilityReproducibility• RuggednessRuggedness
Process Research: CustomersProcess Research: Customers
MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
Process Research: CustomersProcess Research: Customers
MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
responsible for developing In-processassay and critical evaluation of
drug substance and intermediates
Process Research: CustomersProcess Research: Customers
MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
responsible for toxicity studies: (carcinogen, teratogen, gene toxicity)
Process Research: CustomersProcess Research: Customers
MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
responsible for formulatingdrug substance (API) into
drug product
Process Research: CustomersProcess Research: Customers
MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
Oversee process transfer intoPilot plants
Process Research: CustomersProcess Research: Customers
MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
Conducts clinical trials (Ph I-III) and evaluates data
Process Research: CustomersProcess Research: Customers
MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
Discovers new chemical entities (NCE’s) and
prepares intitial quantities
Other CustomersOther Customers
PatentPatent: : drafting, inventorship, litigationdrafting, inventorship, litigation
OutsourcingOutsourcing:: work with vendors on tech work with vendors on tech
transfer; setting specs; qualifyingtransfer; setting specs; qualifying
RegulatoryRegulatory: : drafting of NDA; process drafting of NDA; process
range findingrange finding
Manufacturing:Manufacturing: transfer of processtransfer of process
‘‘know-how’; oversee start-upknow-how’; oversee start-up
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
3. 3. Minimize Hazardous Conditions:Minimize Hazardous Conditions:
Design process to avoid using Design process to avoid using reagents that pose safety threat reagents that pose safety threat
12. 12. Safer Chemistry-Accident Safer Chemistry-Accident Prevention:Prevention:
Design processes that minimize Design processes that minimize hazards to environment and human hazards to environment and human healthhealth
12 Principles of Green Chemistry12 Principles of Green Chemistry
4. 4. Design Safer Products: Design Safer Products:
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
(e.g. drying agents, column (e.g. drying agents, column chromatography)chromatography)
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
ExamplesExamples: avoid extreme cryogenics (-78 : avoid extreme cryogenics (-78 ooC)C)
Avoid prolonged reaction timesAvoid prolonged reaction times
12 Principles of Green Chemistry12 Principles of Green Chemistry
7. 7. Use of Renewable Raw Materials:Use of Renewable Raw Materials:
Use a renewable source rather that Use a renewable source rather that depleting whenever technically and depleting whenever technically and
economically feasible.economically feasible.
example: plant-derived RM; microbial example: plant-derived RM; microbial reactionsreactions
12 Principles of Green Chemistry12 Principles of Green Chemistry
8. 8. Minimize DerivatizationMinimize Derivatization::
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:
Low cost RMLow cost RM Productive/Efficient ReactionsProductive/Efficient Reactions
• High YieldHigh Yield• Highly concentratedHighly concentrated• Few StepsFew Steps• Short time cyclesShort time cycles• Few VesselsFew Vessels
Case Studies from MerckCase Studies from Merck
Remoxipride-----schizophreniaRemoxipride-----schizophrenia Crixivan-----AIDSCrixivan-----AIDS Emend-----Depression, EmesisEmend-----Depression, Emesis L778,123----CancerL778,123----Cancer
Case Study 1: Remoxipride
OMe
Br
NH
O
N
H
OMe
OMe
Br
O
OMe
OHH2N
N
H
Remoxipride
Selective Dopamine-2 Antagonist
Indication: Anti-psychotic (Depression/Schizophrenia)
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
N
N
CONHt-Bu
H2
Pd (OH)2
95% NH
HN
CONHt-Bu
L-PGA
NH
HN
CONHt-Bu
2 L-PGA
47%
86% ee- in ML's
+
NH
HN
CONHt-Bu
2 L-PGA
98 % ee-crystalline salt
95%aq NaOH
Boc2O
KOHNH
BocN
CONHt-Bu
99% ee 80% yield
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
Original Route to cis-Amino Indanol
OH
NH2
OH
NH2
O
NCH3
OCH3CN,H2O2, MeOH CH3CN, CH3SO3H
88% yield 57% yield
racemic cis amino indanol47% yield from indene
1. tartaric acid/MeOH resolution 40% yield 2. NaOH - Salt Break 92% yield
(-) cis amino indanol 100% ee300 kg (15-17% overall yield)
H2O
Drawbacks: Low YieldNo Recycle of (+)-isomer
Asymmetric Route to CAINH2
OH
NH2
OH
O
t-Bu
t-Bu
O
NMn
N
H HO
O
t-Bu
t-Bu
0.7 % S,S-MnII(salen)Cl/aq NaOCl
Tartaric Acid;
Base
(-) CAI
50 % Overall
Catalytic Oxidant:
Oleum, CH3CN;
H2O
78 % @ 87 % ee
> 99 % ee
L
Tetrahedron Lett. 1995, 36, 3993.
SR
Green Chemistry Principles: Prevention (Reduced Waste)Catalysis
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 Acetonide
OH
NH2
COCl
(-)
ON
O
88% yield
aq. KHCO3/IpAc
2-methoxypropene;
MsOH
Amide Enolate Precursor Prepared in High Yield in One Pot Process
1.
2.
Glycidyl Introduction with (S)-Glycidyl Tosylate
OTsO
ON
O
O
ON
OH
O
O N
-25°C
Dimer
O
ON
O
LHMDS
72% yield96% de%
19%
Epoxide
+RS
* (S)-Glycidyl Tosylate: High Cost ($150/kg)
* Two Asymmetric Centers Introduced in a Single Step in High Diastereoselectivity
* Dimer By-Product Also Produced
Tetrahedron Lett. 1994, 35, 673-676.
Glycidyl Introduction with Allylation/Epoxidation
ON
O
Br
O
ON S RO
OON
95 %
Diastereoselectivity = 97:3
LHMDS
2
-35°C
EpoxidizeR
Epoxide Synthesis
O
I
OH
ON
NaOMe
S R
O
OON
87 % (three steps)82% from cis-Aminoindanol
4
99 %O
ON
NCS/NaI
"NIS"
aq NaHCO3
91 %
Epoxidation----Instantaneous reaction: Performed in continuous stirred tank reactor (CSTR) on Manufacturing scale
End Game: Coupling
BocN
NH
t-BuHN OO
OON
12
345+
Piperazine FragmentEpoxide Fragment
N
HN OH
O
OHNH
t-BuHN O
Penultimate94% for 2 steps
1) MeOH, reflux;
2) HCl (g)
End Game: Alkylation
Ot-BuHN
N
HN OH
O
OHNH
N
Cl
t-BuHN O
N
N OH
O
N OHNH
1)
2) H2SO4/ethanol . H2SO4
Penultimate Indinavir Sulfate
Crixivan: Summary
• Overall nine step yield from CAI to sulfate salt is > 60%
• Efficient assembly of optically pure fragments to produce Crixivan®
• Chiral synthesis of cis-aminoindanol via novel Ritter reaction• Diastereoselective syn epoxidation of 2-benzyl-4-enamide
intermediate via the iodohydrin• Novel asymmetric hydrogenation of differentially protected
tetrahydropiperazine• 17,000 gallons of solvent passed through the process train
daily at its peak !
Case Study #3: L778,123
N
N
O
Cl
N
N
CN
N
N
CN
Cl
HN
N
O
Cl
L778,123
ras-Farnesyl transferase Inhibitor (Cancer)
Imidazole Piperazinone
Maligres et al J. Heterocyclic Chem. 2003, 229
Case Study #3: L778,123
N
N
O
Cl
N
N
CN
N
N
CN
Cl
HN
N
O
Cl
L778,123
ras-Farnesyl transferase Inhibitor (Cancer)
Imidazole Piperazinone
Maligres et al J. Heterocyclic Chem. 2003, 229
Med Chem Route: Imidazole
N
N
CN
CHO
N
NOH
1. Tr-Cl
2. Ac2O
91%
N
NOAc
TrN
NOAc
CN
HBr
1. ArCH2Br
2. MeOH
LiOH/aq THF
N
NOH
CN
SO3-pyr
66% 80%
Drawbacks: (1) costly starting material; (2) double protection/deprotection
Marckwald Route to Imidazole
N
N
CN
Cl
N
N
CN
OHHS
NH2
CN
SCN OH
OHO
Delapine/Marckwald Route
NH2-H3PO4
CN
Br
CN
NN
NN
EtOH/80 oC
N
CN
H3PO4
88%
HOHO
OKSCN
aq MeCN
60-70 oC
N
NHS
OH
CN82% yield
Delapine/Marckwald Route
NH2-H3PO4
CN
Br
CN
NN
NN
EtOH/80 oC
N
CN
H3PO4
88%
HOHO
OKSCN
aq MeCN
60-70 oC
N
NHS
OH
CN82% yield
N
NH
OH
CN
conc HNO3
Fe (III)
Raney Ni
Dethionation: Green Approach
NH2-H3PO4
CN
Br
CN
NN
NN
EtOH/80 oC
N
CN
H3PO4
88%
HOHO
OKSCN
aq MeCN
60-70 oC
N
NHS
OH
CN82% yield
N
NH
OH
CN
H2O2aq AcOH
35-40 oC
90 %
Green Principles: Prevention/Degradation
Case Study #3: L778,123
N
N
O
Cl
N
N
CN
N
N
CN
Cl
HN
N
O
Cl
L778,123
ras-Farnesyl transferase Inhibitor (Cancer)
Imidazole Piperazinone
Maligres et al J. Heterocyclic Chem. 2003, 229
Med Chem Route: Piperazinone
N O
O NH2-HCl
Cl
+160 oC
-CO2
HN
Cl
NH2-HCl
Boc2O
HN
Cl
NHBoc
ClCl
O
N
Cl
NHBocCl
O
Et3N/DCM
K2CO3
N
N
Ar
O
Boc
DMF
22% yieldSiO2 purification
80%
HCl (g)
-78 oCN
N
Ar
O
HHCl
Piperazinone:New Route
Weissman et. al. Tetrahedron Lett. 1998, 7459
NH2
Cl
ClCl
O
aq KHCO3
NH
Cl
Cl
O
NH2
OH
5 oC60 oC/2 h
NH
Cl
HN
O OH
70%
N
Cl
HN
O
DIADR3PEtOAc1 h/RT
87%
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
Industry ChallengesIndustry Challenges Increased Regulatory controls (FDA, Increased Regulatory controls (FDA,
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
1,3-Asymmetric Induction
R1
NMe2
O
R2
R1 = Me, BnR2 = H, Me
I2
aq DMEOR2
I
R2
O
trans selectivity 90-99%
Yoshida JACS 1984, 1079
pH Dependence of Outcome
O
ON
O
ON
I
I2 H2O-THF
OI
O
OHH2N
2
+
High trans selectivity
pH < 7
O
ON
I OH
pH Dependence of Outcome
O
ON
O
ON
I
I2 H2O-THF
OI
O
OHH2N
+
High trans selectivity
pH < 7
O
ON
I OH
pH > 7
O
ON
OH
I
Marckwald Mechanism
O
OHOH
ArCH2NH2
ArCH2N
OHOH
ArCH2N
OOH
NCS
ArCH2N
OHOH
N=C=S
N
N
S
Ar
HO
HO
B:
H
H+
N
N
S
Ar
HO
N
N
SH
Ar
HO