process chemistry lecture-1

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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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.


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.

process chemistry lecture-1

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