process chemistry lecture-1
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8/13/2019 Process Chemistry Lecture-1
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Process Chemistry
Alex Joseph
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Outline
What is Process Chemistry?
Drug Development Timeline and Cost
General Considerations
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What is Process Chemistry?
Safe
Environmentallyfriendly
Efficient
Economical($ and atom)
Process chemistry- refers to development work that is carried out in thepharmaceutical industry in pursuit of safe, efficient, economical, andenvironmentally friendly syntheses of complex molecules for use intreating human disease.
The mission of process chemistry in the pharmaceutical industry is toprovide documented, controlled synthetic processes for the manufactureof an active pharmaceutical ingredient (API) or the drug.
Why is synthesis and process research needed sincethere already exists a synthesis established by discoverychemistry about the way to find the clinical candidate?
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Synthetic strategies: Discovery chemistry vs Synt. & Proc. Research
Diversity vs target orientation
The goal of discovery chemistrythe task of medicinal chemistsis tosynthesize as many new compounds as quickly as possible, which will
then be tested by biologists against the chosen biological target.- diversityoriented process
After the identification of a new clinical candidate. The task now is to developa specific synthetic process for a large-scale production process whichshould be safe, efficient, economical, and environmentally friendly.
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Drug Development Timeline Average of 12-15 yrs
TargetScreen(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 yrs
200-300 gms < 100 kg 100-2000 kg
8.2 years
Process research begin as soon as a hit compound is found till after launch if necessary.Two time periods process chemistry can significantly shorten are the period between thelead candidate optimization to the clinical trials and the time at the end of the clinicaltrials to the launch of the drug on the market.Reduced timeline of process research would allow for an early launch into the marketwith minimal costs.
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Patent protection for20 years
Need For Efficient Process Chemistry
http://www.fda.gov/cder/index.html
Generic drug application:Abbreviated New DrugApplication (ANDA)
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Presidential Green Chemistry
Challenge Award Established in 1995 by the US-EPA For innovations in cleaner, cheaper and smarter
chemistry
HN
N
O
H2N
N
N
OOH
HO
Cytovene2000 Roche Corp.Reduced liquid waste:1120 metric tons / yearReduced solid waste:25 metric tons / year
HN
Cl
Cl
HCl
Zoloft2002 Pfizer, Inc.
Reduced waste:
HCl (conc): 150 metric tons / year
TiO2: 440 metric tons / year
HN
HN N
O
N
O O
F
CF3
CF3
Emend2005 MerckReduced waste:
340,000 L / metric ton
Sertraline hydrochloride
Ganciclovir
Aprepitant
Anti-emitic
Principles of process and green Chemistry1. Prevention.(waste)
2. AtomEconomy.
3. Less Hazardous Chemical Synthesis.
4. Designing Safer Chemicals.
5. Safer Solvents and Auxiliaries.
6. Design for Energy Efficiency. Energy requirements should be minimized
7. Use of Renewable raw material. A raw material or feedstock should be renewable rather than depleting
8. ReduceDerivatives. Unnecessary derivatization.
9. Catalysis. Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.
10. Design for Degradation. Chemical products should be designed so that at the end of their function they
do not persist in the environment and instead break down into harmless degradation products.
11. Real-time Analysis for Pollution Prevention. in-process monitoring and control prior to the formation of
hazardous substances.
12. Inherently Safer Chemistry for Accident Prevention. Substance used in a chemical process should be
chosen so as to minimize the potential for chemical accidents, including releases, explosions.
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General Considerations for Process Chemistry
Avoid column chromatography
Seeding helps crystallization
Avoid desiccants, use azeotrope
Avoid solvents with flash point < 15 C
Ether, hexanes, DCM
Temperature range -40 to 120 C
Avoid protecting groups
Impurities of > 0.1% must be analyzed
1. Prevention
It is better to prevent waste than to treat or
clean up waste after it is formed.
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2. Atom Economy
Synthetic methods should be designed to
maximize the incorporation of all materials
used in the process into the final product.
Organic Chemistry & Percent Yield
Epoxidation of an alkene using a peroxyacid
O O
OH
Cl
+
O
100% yield
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Percent yield:
Percent yield:
% yield = (actual yield/theoretical yield) x 100
What is missing?
What co-products are made?
How much waste is generated?
Is the waste benign waste?
Are the co-products benign and/or useable?
How much energy is required?
Are purification steps needed?
What solvents are used? (are they benign and/or reusable?
Is the catalyst truly a catalyst? (stoichiometric vs. catalytic?)
Balanced Reactions
Balanced chemical reaction of the epoxidation of styrene
O O
OH
Cl
+
O
+
O OH
Cl
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Balanced chemical reaction of the epoxidation of styrene
Assume 100% yield.
100% of the desired epoxide product is recovered.100% formation of the co-product: m-chlorobenzoic acid
A.E. of this reaction is 43%.57% of the products are waste.
Atom Economy
% AE = (FW of atoms utilized/FW of all reactants) X 100
3. Less Hazardous Chemical
Synthesis
Whenever practicable, syntheticmethodologies should be designed touse and generate substances thatpossess little or no toxicity to human
health and the environment.
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Less Hazardous Chemical Synthesis
Disadvantages
phosgene is highly toxic, corrosive
requires large amount of CH2Cl2 polycarbonate contaminated with Cl impurities
OH OH
Cl Cl
O
+ NaOH
O O *
O
* n
Polycarbonate Synthesis: Phosgene Process
Less Hazardous Chemical Synthesis
OH OH
+ O O *
O
* n
O O
O
Advantages
diphenylcarbonate - synthesized without phosgene
eliminates use of CH2Cl2 higher-quality polycarbonates
Polycarbonate Synthesis: Solid-State Process
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4. Designing Safer Chemicals
Chemical products should be designedto preserve efficacy of the function whilereducing toxicity.
Designing Safer Chemicals:Case Study: Antifoulants
Antifoulants are generally dispersed in the paint as it isapplied to the hull. Organotin compounds havetraditionally been used, particularly tributyltin oxide(TBTO). TBTO works by gradually leaching from thehull killing the fouling organisms in the surroundingarea
TBTO and other organotin antifoulants have long half-lives in the environment (half-life of TBTO in seawater
is > 6 months). They also bioconcentrate in marineorganisms (the concentration of TBTO in marineorganisms to be 104 times greater than in thesurrounding water).
Organotin compounds are chronically toxic to marinelife and can enter food chain. They arebioaccumulative.
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Designing Safer Chemicals:Case Study: Antifoulants
Sea-Nine 211
Rohm and Haas
Presidential Green Chemistry Challenge Award, 1996
The active ingredient in Sea-Nine 211, 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOI), is a member of the isothiazolone familyof antifoulants.
Designing Safer Chemicals:Case Study: Antifoulants
Sea-Nine 211 works by maintaining a hostile growing environment formarine organisms. When organisms attach to the hull (treated withDCOI), proteins at the point of attachment with the hull react with theDCOI. This reaction with the DCOI prevents the use of theseproteins for other metabolic processes. The organism thus detachesitself and searches for a more hospitable surface on which to grow.
Only organisms attached to hull of ship are exposed to toxic levels ofDCOI.
Readily biodegrades once leached from ship (half-life is less than onehour in sea water).
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5. Safer Solvents and
AuxiliariesThe use of auxiliary substances(solvents, separation agents, etc.) shouldbe avoided whenever possible and,when used,should be used judiciously.
Safer Solvents
Solvent Substitution
Water as a solvent
New solvents
Ionic liquidsSupercritical fluids
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Preferred Useable Undesirable
Water Cyclohexane PentaneAcetone Heptane Hexane(s)
Ethanol Toluene Di-isopropyl ether
2-Propanol Methylcyclohexane Diethyl ether
1-Propanol Methyl t-butyl ether Dichloromethane
Ethyl acetate Isooctane Dichloroethane
Isopropyl acetate Acetonitrile Chloroform
Methanol 2-MethylTHF Dimethyl formamide
Methyl ethyl ketone Tetrahydrofuran N-Methylpyrrolidinone
1-Butanol Xylenes Pyridine
t-Butanol Dimethyl sulfoxide Dimethyl acetate
Acetic acid Dioxane
Ethylene glycol Dimethoxyethane
Benzene
Carbon tetrachloride
Solvent Selection
Red Solvent Reason
Pentane Very low flash point, good alternative available.
Hexane(s) More toxic than the alternative heptane
Di-isopropyl ether Very powerful peroxide former, good alternative ethers available.
Diethyl ether Very low flash point, good alternative ethers available.
Dichloromethane High volume use, regulated by EU solvent directive
Dichloroethane Carcinogen
Chloroform Carcinogen
Dimethyl formamide Toxicity, strongly regulated by EU Solvent Directive
N-Methylpyrrolidinone Toxicity, strongly regulated by EU Solvent Directive.
Pyridine Carcinogenic/mutagenic/reprotoxic carcinogen, toxicity, very low thresholdlimit value (TLV) for worker exposures.
Dimethyl acetate Toxicity, strongly regulated by EU Solvent Directive.
Dioxane carcinogen
Dimethoxyethane carcinogen, toxicity.
Benzene Avoid use toxic to humans and environment, very low TLV (0.5 ppm),
strongly regulated in EU.
Carbon tetrachloride Avoid use: carcinogen, toxic, ozone depletor, not available for large-scale
use, strongly regulated in the EU.
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6. Design for Energy
EfficiencyEnergy requirements should berecognized for their environmental andeconomic impacts and should beminimized. Synthetic methods should beconducted at ambient temperature andpressure.
Energy in a chemical process
Thermal (electric)
Cooling
Distillation
Equipment (lab hood)
Microwave
Source of energy:
Power plantcoal, oil, natural gas
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Energy usage
Chemicals and petroleum industries account for 50% of industrialenergy usage.
~1/4 of the energy used is consumed in distillation and dryingprocesses.
Alternative energy sources: Photochemical Reactions
Two commercial photochemical processes (Caprolactam process & vitamin D3)
Caprolactam process
NOClNO+ Cl (535nm)
+ Cl + HCl
+ NO
NO
NO
+ 2 HCl
NOH.2HCl
NOH.2HClN
O
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Alternative Energy Sources:Microwave chemistry
Wavelengths between 1 mm and 1 m
More directed source of energy
Heating rate of 10C per second is achievable
Possibility of overheating (explosions)
Solvent-free conditions are possible
Interaction with matter characterized by penetration depth
7. Use of RenewableFeedstocks
A raw material or feedstock should berenewable rather than depletingwhenever technically and economicallypractical.
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Polymers from Renewable Resources:
Fermentation of glucose in the presence of bacteria and propanoic acid(product contains 5-20% polyhydroxyvalerate)
Similar to polypropene and polyethene
Biodegradable (credit card)
O
HO
OH
OH
OH
OH
Alcaligenes eutrophus
propanoic acid
R
O
O
R = Me, polydroxybutyrate
R = Et, polyhydroxyvalerate
n
Raw Materials from Renewable Resources:The BioFine Process
O
HO
O
Paper millsludge
Levulinic acid
Municipal solid wasteand waste paper
Agriculturalresidues,Waste wood
Green Chemistry Challenge Award1999 Small Business Award
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Levulinic acid as a platform chemical
O
HO
O
O
H2N
OH
O
O
HO
DALA (-amino levulinic acid)(non-toxic, biodegradable herbicide)
O
HO
O
OH
C
CH3
C
H2
C
H2
C
O
OHHO
Diphenolic acid
Acrylic acidSuccinic acid
O
THF
O
MTHF(fuel additive)
HO
OH
butanediol
OO
gammabutyrolactone
8. Reduce Derivatives
Unnecessary derivatization (blockinggroup, protection/deprotection,temporary modification ofphysical/chemical processes) should be
avoided whenever possible.
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Protecting Groups
2 synthetic steps are added each time one is used
Overall yield and atom economy will decrease
Protecting groups are used because there is no direct way to solve the
problem without them.
9. Catalysis
Catalytic reagents (as selective aspossible) are superior to stoichiometricreagents.
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Heterogeneous vs Homogenous
Distinct solid phase
Readily separated
Readily regenerated &
recycled
Rates not as fast
Diffusion limited
Lower selectivity
Long service life
High energy process Poor mechanistic
understanding
Same phase as rxn medium
Difficult to separate
Expensive and/or difficult toseparate
Very high rates
Not diffusion controlled
High selectivity
Short service life
Mild conditions Mechanisms well understood
Biocatalysis
Enzymes or whole-cell microorganisms
Benefits Substrate specificity: Only one specific reaction step is normally
catalyzed by an enzyme.
Site specificity (regiospecificity
Stereospecificity and selectivity
Rection in water
Naturally occurring
Moderate conditions
Possibility for tandem rxns (one-pot)
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10. Design for Degradation
Chemical products should be designedso that at the end of their function theydo not persist in the environment andinstead break down into harmlessdegradation products.
11. Real-time Analysis for
Pollution Prevention
Analytical methodologies need to befurther developed to allow for real-timein-process monitoring and control prior tothe formation of hazardous substances.
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Real time analysis for a chemist is theprocess of checking the progress of
chemical reactions as it happens.
Knowing when your product is
done can save a lot of waste,
time and energy!
12. Inherently Safer Chemistry
for Accident Prevention
Substance and the form of a substanceused in a chemical process should bechosen so as to minimize the potentialfor chemical accidents, including
releases, explosions, and fires.
Chemists try to avoid things that explode,light on fire, are air-sensitive, etc.
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