Download - Green Chemistry Principles

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)


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


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


MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

responsible for developing In-processassay and critical evaluation of

drug substance and intermediates


MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

responsible for toxicity studies: (carcinogen, teratogen, gene toxicity)


MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

responsible for formulatingdrug substance (API) into

drug product


MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

Oversee process transfer intoPilot plants


MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

Conducts clinical trials (Ph I-III) and evaluates data


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


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.


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%


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


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


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)


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


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


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.


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


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


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)


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


5

2

41

3

NNH OH

O

OHN

t-BuHN O

N

Crixivan


3-Picolyl Chloride

N

Cl

BocN

NH

t-BuHN O

H2N OH

O

ON

O 12

345+


ON

O

Allyl Bromide

Br


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


5

2

41

3

NNH OH

O

OHN

t-BuHN O

N

Crixivan


3-Picolyl Chloride

N

Cl

BocN

NH

t-BuHN O

H2N OH

O

ON

O 12

345+


ON

O

Allyl Bromide

Br


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+


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

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

http://www.amazon.com/exec/obidos/search-handle-url/index=books&field-author=Anderson%2C%20Neal/002-6558130-6484838

http://www.amazon.com/exec/obidos/search-handle-url/index=books&field-author=Hawthorne%2C%20Fran/002-6558130-6484838

http://www.amazon.com/exec/obidos/search-handle-url/index=books&field-author=Pisano%2C%20Gary%20P./002-6558130-6484838

http://www.amazon.com/exec/obidos/search-handle-url/index=books&field-author=Pisano%2C%20Gary%20P./002-6558130-6484838

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

Download - Green Chemistry Principles

Top Related