patrick an introduction to medicinal chemistry 3/e chapter 12 drug design & development

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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal

ChemistryChemistry 3/e 3/e

Chapter 12 Chapter 12

DRUG DESIGN & DRUG DESIGN & DEVELOPMENTDEVELOPMENT

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ContentsContents1. Preclinical trials

1.1. Chemical Development (2 Slides)1.2. The Initial Synthesis (3 Slides)1.3. Optimisation of Reactions

1.3.1. Temperature1.3.2. Pressure (2 Slides)1.3.3. Reaction Time1.3.4. Solvent (3 Slides)1.3.5. Concentration1.3.6. Catalysts (2 Slides)1.3.7. Excess Reactant1.3.8. Removing a Product1.3.9. Methods of Addition (2

Slides)1.3.10. Reactivity of Reagents &

Reactants1.4. Scaling Up A Reaction

1.4.1. Reagents (3 Slides)1.4.2. Reactants And

Intermediates1.4.3. Solvents (4 Slides)1.4.4. Side Products1.4.5. Temperature1.4.6. Promoters1.4.7. Experimental Procedures

(2 Slides)1.4.8. Physical Para Meters

continued…continued…1.5. Process Development

1.5.1. Number Of Reaction Steps

1.5.2. Convergent Syntheses1.5.3. Number Of Operations1.5.4. Safety - Chemical

Hazards1.5.4.1. Main

Hazards1.5.5. Safety - Reaction

Hazards1.5.6. Purifications1.5.7. Environmental Issues1.5.8. Cost

1.6. Specifications1.6.1. Properties And Purity1.6.2. Impurities1.6.3. Purifications1.6.4. Impure Reagents /

Reactants (3 Slides)1.6.5. Reaction Conditions1.6.6. Order Of Addition1.6.7. Troublesome By-

Products (2 Slides)1.6.8. Changing A Synthesis

(2 Slides)1.6.9. Inorganic Impurities

2. Patenting And Regulatory Affairs3. Clinical Trials (2 Slides)

[67 slides]

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Drug design and developmentDrug design and development Stages:Stages:

1) Identify target disease1) Identify target disease 2) Identify drug target2) Identify drug target 3) Establish testing procedures3) Establish testing procedures 4) Find a lead compound4) Find a lead compound 5) Structure Activity Relationships (SAR)5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore6) Identify a pharmacophore 7) Drug design- optimising target interactions7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties8) Drug design - optimising pharmacokinetic properties 9) Preclinical trials9) Preclinical trials10) Chemical development and process development10) Chemical development and process development11) Patenting and regulatory affairs11) Patenting and regulatory affairs12) Clinical trials12) Clinical trials

Note: Note: Stages 9-11 are usually carried out in parallelStages 9-11 are usually carried out in parallel

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Drug MetabolismDrug MetabolismIdentification of drug metabolites in test animals Identification of drug metabolites in test animals

Properties of drug metabolitesProperties of drug metabolites

ToxicologyToxicologyIn vivoIn vivo and and in vitroin vitro tests for acute and chronic tests for acute and chronic toxicity toxicity

PharmacologyPharmacologySelectivity of action at drug targetSelectivity of action at drug target

FormulationFormulationStability testsStability testsMethods of deliveryMethods of delivery

1. Preclinical trials1. Preclinical trials

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Definition:Definition:Development of a synthesis suitable for large scale Development of a synthesis suitable for large scale

production up to 100kg.production up to 100kg.

1.1 Chemical Development1.1 Chemical Development

Priorities:Priorities:• To optimise the final synthetic step and the purification To optimise the final synthetic step and the purification

procedures procedures • To define the product specifications To define the product specifications • To produce a product that consistently passes the purity To produce a product that consistently passes the purity

specifications specifications • To produce a high quality product in high yield using a synthesis To produce a high quality product in high yield using a synthesis

that is cheap and efficient. that is cheap and efficient. • To produce a synthesis that is safe and environmentally friendly To produce a synthesis that is safe and environmentally friendly

with a minimum number of stepswith a minimum number of steps

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Phases:Phases: • Synthesis of 1kg for initial preclinical testing (often a scale up of the Synthesis of 1kg for initial preclinical testing (often a scale up of the

original synthesis) original synthesis) • Synthesis of 10kg for toxicological studies, formulation and initial Synthesis of 10kg for toxicological studies, formulation and initial

clinical trialsclinical trials• Synthesis of 100kg for clinical trialsSynthesis of 100kg for clinical trials

Notes:Notes:• Chemical development is more than just scaling up the original Chemical development is more than just scaling up the original

synthesissynthesis• Different reaction conditions or synthetic routes often requiredDifferent reaction conditions or synthetic routes often required• Time period can be up to 5 yearsTime period can be up to 5 years• Need to balance long term aims of developing a large scale Need to balance long term aims of developing a large scale

synthesis versus short term need for batches for preclinical trialssynthesis versus short term need for batches for preclinical trials• The product produced by the fully developed route must meet the The product produced by the fully developed route must meet the

same specifications as defined at phase 1same specifications as defined at phase 1

1.1 Chemical Development1.1 Chemical Development

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OriginOrigin • The initial synthesis was designed in the research labThe initial synthesis was designed in the research labPrioritiesPriorities of the original synthesisof the original synthesis• To synthesise as many different compounds as quickly as possible in To synthesise as many different compounds as quickly as possible in

order to identify active compoundsorder to identify active compounds• Yield and cost are low prioritiesYield and cost are low priorities• usually done on small scaleusually done on small scaleLikely problems related to the original synthesisLikely problems related to the original synthesis• The use of hazardous starting materials and reagents The use of hazardous starting materials and reagents • Experimental procedures which are impractical on large scaleExperimental procedures which are impractical on large scale• the number of reaction steps involvedthe number of reaction steps involved• Yield and costYield and costScale upScale up • Original synthesis may be scaled up for the first 1 kg of product but is Original synthesis may be scaled up for the first 1 kg of product but is

then modified or altered completely for larger quantitiesthen modified or altered completely for larger quantities

1.2 The initial synthesis1.2 The initial synthesis

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The initial synthesis of fexofenadine (anti-asthmatic)The initial synthesis of fexofenadine (anti-asthmatic)

• Fexofenadine synthesised by the same route used for terfenadineFexofenadine synthesised by the same route used for terfenadine• Unsatisfactory since the Friedel Crafts reaction gives the Unsatisfactory since the Friedel Crafts reaction gives the metameta isomer as well isomer as well• Requires chromatography to remove the Requires chromatography to remove the metameta isomer isomer

CR

MeMeC

R2N

O

Reduction NHO

Ph Ph

HOC

R

MeMe

R= Me; TerfenadineR=CO2H; Fexofenadine

CR

MeMe

CO

Cl

ClC

R

MeMeC

Cl

O

Friedel CraftsAcylation

R2NH


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Revised synthesis of fexofenadineRevised synthesis of fexofenadine

• More practical and efficient synthesis using easily available starting materialsMore practical and efficient synthesis using easily available starting materials• No ‘awkward’ isomers are formedNo ‘awkward’ isomers are formed• No chromatography required for purificationNo chromatography required for purification

CCO2Et

Me

Me

Me

OxidationC

CO2Et

Me

OHC

Me

O

O

MgBr

NHHO

PhPh

1)

2) NaBH4

NHO

Ph Ph

HOC

CO2Et

MeMe

CCO2Et

MeMe

OH

O

O

CO2Et

MeMe

O

HO

Esterhydrolysis

Fexofenadine

Amberlyst


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Aims:Aims: • To optimise the yield and purity of product from each reactionTo optimise the yield and purity of product from each reaction

Notes:Notes: • Maximum yield does not necessarily mean maximum purityMaximum yield does not necessarily mean maximum purity• May need to accept less than the maximum yield to achieve an May need to accept less than the maximum yield to achieve an

acceptable purity acceptable purity • Need to consider cost and safetyNeed to consider cost and safety

Factors:Factors: • Temperature, reaction time, stirring rate, pH, pressure, Temperature, reaction time, stirring rate, pH, pressure,

catalysts, order and rate of addition of reactants and reagents, catalysts, order and rate of addition of reactants and reagents, purification procedure. purification procedure.

1.3 Optimisation of reactions1.3 Optimisation of reactions

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• Optimum temperature is the temperature at which the rate of Optimum temperature is the temperature at which the rate of reaction is maximised with a minimum of side reactionsreaction is maximised with a minimum of side reactions

• Increasing the temperature increases the reaction rateIncreasing the temperature increases the reaction rate• Increasing the temperature may increase side reactions and Increasing the temperature may increase side reactions and

increase impuritiesincrease impurities• Compromise is often requiredCompromise is often required

1.3.1 Temperature1.3.1 Temperature


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• Increased pressure (> 5 kilobar) accelerates reactions where the Increased pressure (> 5 kilobar) accelerates reactions where the transition state occupies a smaller volume than the starting transition state occupies a smaller volume than the starting materials.materials.

• Useful if increased heating causes side reactionsUseful if increased heating causes side reactions

Examples of reactions accelerated by pressure Examples of reactions accelerated by pressure • Esterifications; amine quaternisation; ester hydrolysis; Claisen Esterifications; amine quaternisation; ester hydrolysis; Claisen

and Cope rearrangements; nucleophilic substitutions; Diels and Cope rearrangements; nucleophilic substitutions; Diels Alder reactionsAlder reactions

Example: Example: Esterification of acetic acid with ethanol Esterification of acetic acid with ethanol • proceeds 5 times faster at 2 kbar than at 1 atm.proceeds 5 times faster at 2 kbar than at 1 atm.• proceeds 26 times faster at 4 kbarproceeds 26 times faster at 4 kbar

1.3.2 Pressure1.3.2 Pressure


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Br

OOPPh3

PPh3

OO

benzene-toluene20oC / 15,000atm

• Good yield at 20Good yield at 20ooC and 15 kbarC and 15 kbar• No reaction at 20No reaction at 20ooC and 1 atmosphereC and 1 atmosphere• Decomposition at 80Decomposition at 80ooC and 1 atmosphereC and 1 atmosphere

Example 1:Example 1:

Example 2:Example 2:• Hydrolysis of chiral esters using base with heating may cause Hydrolysis of chiral esters using base with heating may cause

racemisationracemisation• Can be carried out at room temperature with pressure insteadCan be carried out at room temperature with pressure instead

1.3.2 Pressure1.3.2 Pressure


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• Optimum reaction time is the time required to get the best yield Optimum reaction time is the time required to get the best yield consistent with high purity. consistent with high purity.

• Monitor reactions to find the optimum time using tlc, gas Monitor reactions to find the optimum time using tlc, gas chromatography, IR, NMR, HPLCchromatography, IR, NMR, HPLC

• If reaction goes to completion, optimum time is often the time If reaction goes to completion, optimum time is often the time required to reach completionrequired to reach completion

• If reaction reaches equilibrium, optimum time is often the time If reaction reaches equilibrium, optimum time is often the time required to reach equilibriumrequired to reach equilibrium

• However, optimum time may not be the same as the time to reach However, optimum time may not be the same as the time to reach completion or equilibrium if side reactions take placecompletion or equilibrium if side reactions take place

• Excess reaction times increase the chances of side reactions and Excess reaction times increase the chances of side reactions and the formation of impurities.the formation of impurities.

• Reaction times greater than 15 hr should be avoided (costly at Reaction times greater than 15 hr should be avoided (costly at production level)production level)

1.3.3 Reaction time1.3.3 Reaction time


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• Important to outcome, yield and purityImportant to outcome, yield and purity• Should normally be capable of dissolving reactants and reagentsShould normally be capable of dissolving reactants and reagents• Insolubility of a product in solvent may improve yields by shifting an Insolubility of a product in solvent may improve yields by shifting an

equilibrium reaction to its products (but this may be a problem with equilibrium reaction to its products (but this may be a problem with catalysts)catalysts)

C

HN

NH

O

O

OO

O

OH

H

H H2 Pd/C

EtOH/H2O

H3NNH

O

O

O

OH

H

H

• Poor yield in ethanol - product precipitates and coats the catalystPoor yield in ethanol - product precipitates and coats the catalyst• Poor yield in water - reactant poorly solublePoor yield in water - reactant poorly soluble• Quantitative yield in ethanol-water; 1:1Quantitative yield in ethanol-water; 1:1

Example:Example:

1.3.4 Solvent1.3.4 Solvent1.3 Optimisation of reactions1.3 Optimisation of reactions

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• Should have a suitable boiling point if one wishes to heat the Should have a suitable boiling point if one wishes to heat the reaction at a constant temperature (heating to reflux)reaction at a constant temperature (heating to reflux)

• Should be compatible with the reaction being carried outShould be compatible with the reaction being carried out• Solvents are classed as polar (EtOH, HSolvents are classed as polar (EtOH, H22O, acetone) or O, acetone) or

nonpolar (toluene, chloroform)nonpolar (toluene, chloroform)• Polar solvents are classed as protic (EtOH, HPolar solvents are classed as protic (EtOH, H22O) or aprotic O) or aprotic

(DMF, DMSO)(DMF, DMSO)• Protic solvents are capable of H-bondingProtic solvents are capable of H-bonding• The polarity and the H-bonding ability of the solvent may The polarity and the H-bonding ability of the solvent may

affect the reactionaffect the reaction

1.3 Optimisation of reactions1.3 Optimisation of reactions1.3.4 Solvent1.3.4 Solvent

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• Solvent DMSO; reaction time 1-2 hoursSolvent DMSO; reaction time 1-2 hours• Solvent aq. ethanol; reaction time 1-4 daysSolvent aq. ethanol; reaction time 1-4 days• DMSO solvates cations but leaves anions relatively DMSO solvates cations but leaves anions relatively

unsolvatedunsolvated• Thus, the nucleophile is more reactiveThus, the nucleophile is more reactive

RCl

RCN

NaCNDMSO

Example:Example:• Protic solvents give higher rates for SProtic solvents give higher rates for SNN1 reactions but not for S1 reactions but not for SNN2 2

reactions - they aid departure of anion in the rate determining stepreactions - they aid departure of anion in the rate determining step• Dipolar aprotic solvents (DMSO) are better for SDipolar aprotic solvents (DMSO) are better for SNN2 reactions2 reactions

SSNN2 reaction2 reaction

1.3 Optimisation of reactions1.3 Optimisation of reactions1.3.4 Solvent1.3.4 Solvent

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• High concentration (small volume of solvent) favours High concentration (small volume of solvent) favours increased reaction rate but may increase chance of side increased reaction rate but may increase chance of side reactionsreactions

• Low concentrations (large volume of solvent) are useful for Low concentrations (large volume of solvent) are useful for exothermic reactions (solvent acts as a ‘heat sink’)exothermic reactions (solvent acts as a ‘heat sink’)

1.3.5 Concentration1.3.5 Concentration


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• Increase rate at which reactions reach equilibriumIncrease rate at which reactions reach equilibrium• Classed as heterogeneous or homogeneousClassed as heterogeneous or homogeneous• Choice of catalyst can influence type of product obtained and Choice of catalyst can influence type of product obtained and

yieldyield

R C C R R C C RH

H

H

H

H2 Pd/C

Example:Example:

R C C R C CR

H

R

H

H2 Pd/CaCO 3

Poisonedcatalyst

1.3.6 Catalysts1.3.6 Catalysts


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R Cl RC

O

R

CR

O

Lewis acid

Vary Lewis acid catalysts (e.g. AlClVary Lewis acid catalysts (e.g. AlCl33 or ZnCl or ZnCl22) to optimise yield and ) to optimise yield and puritypurity

Example:Example:

1.3 Optimisation of reactions1.3 Optimisation of reactions1.3.6 Catalysts1.3.6 Catalysts

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• Shifts equilibrium to products if reaction is thermodynamically Shifts equilibrium to products if reaction is thermodynamically controlledcontrolled

• Excess reactant must be cheap, readily available and easily Excess reactant must be cheap, readily available and easily separated from productseparated from product

• May also affect outcome of reactionMay also affect outcome of reaction

Ph O

O

H2NNH2

HN

NH2C

O

Ph

O

+ HN

NH

C

O

C

O

• Excess diamine is used to increase the proportion of mono-acylated productExcess diamine is used to increase the proportion of mono-acylated product

Example:Example:

1.3.7 Excess reactant1.3.7 Excess reactant


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• Removing a product shifts the equilibrium to products if the Removing a product shifts the equilibrium to products if the reaction is in equilibriumreaction is in equilibrium

• Can remove a product by precipitation, distillation or Can remove a product by precipitation, distillation or crystallisationcrystallisation

Removing water by distillation shifts equilibrium to rightRemoving water by distillation shifts equilibrium to right

R R

O

HOOH

R R

OO+Ptsa catalyst

+ H2O

Example:Example:

1.3.8 Removing a product1.3.8 Removing a product


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• Adding one reactant or reagent slowly to another helps to Adding one reactant or reagent slowly to another helps to control the temperature of fast exothermic reactionscontrol the temperature of fast exothermic reactions

• Stirring rates may be crucial to prevent localised regions of Stirring rates may be crucial to prevent localised regions of high concentrationhigh concentration

• Dilution of reactant or reagent in solvent before addition Dilution of reactant or reagent in solvent before addition helps to prevent localised areas of high concentration helps to prevent localised areas of high concentration

• Order of addition may influence the outcome and yieldOrder of addition may influence the outcome and yield

+

1.3.9 Methods of addition1.3.9 Methods of addition


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• Impurity is formed when butyl lithium is added to the Impurity is formed when butyl lithium is added to the phosphonate (the phosphonate anion reacts with unreacted phosphonate (the phosphonate anion reacts with unreacted phosphonate)phosphonate)

• No impurity is formed if the phosphonate is added to butyl lithiumNo impurity is formed if the phosphonate is added to butyl lithium

N

Ar

P

O

OMe

OMeN

Ar

R N

Ar

R

1) nBuLi2) RCHO

impurity

+

Example:Example:

1.3 Optimisation of reactions1.3 Optimisation of reactions1.3.9 Methods of addition1.3.9 Methods of addition

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Less reactive reagents may affect the outcome of the reactionLess reactive reagents may affect the outcome of the reaction

• A 1:1 mixture of mono and diacylated products is obtained even when A 1:1 mixture of mono and diacylated products is obtained even when benzyl chloride is added to the diaminebenzyl chloride is added to the diamine

• Using less reactive benzoic anhydride gives a ratio of mono to diacylated Using less reactive benzoic anhydride gives a ratio of mono to diacylated product of 1.86:0.14product of 1.86:0.14

Cl

O

H2NNH2

HN

NH2C

O

+ HN

NH

C

O

C

O

Example:Example:

1.3.10 Reactivity of reagents and reactants1.3.10 Reactivity of reagents and reactants1.3 Optimisation of reactions1.3 Optimisation of reactions

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PrioritiesPrioritiesCost, safety and practicalityCost, safety and practicality

Factors to considerFactors to consider Reagents, reactants and intermediates, solvents, side products, Reagents, reactants and intermediates, solvents, side products, temperature, promoters, procedures, physical parameterstemperature, promoters, procedures, physical parameters

1.4 Scaling up a reaction1.4 Scaling up a reaction

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• Reagents used in the initial synthesis are often unsuitable due to Reagents used in the initial synthesis are often unsuitable due to cost or hazards. cost or hazards.

• Hazardous by products may be formed from certain reagents (e.g. Hazardous by products may be formed from certain reagents (e.g. mercuric acetate from mercury)mercuric acetate from mercury)

• Reagents may be unsuitable on environmental grounds (e.g. smell)Reagents may be unsuitable on environmental grounds (e.g. smell)• Reagents may be unsuitable to handle on large scale (e.g. Reagents may be unsuitable to handle on large scale (e.g.

hygroscopic or lachrymatory compounds)hygroscopic or lachrymatory compounds)

H

RR

H HRR

HZn/CuEt2OCH2I2

Example:Example:

• Zn/Cu amalgam is too expensive for scale up Zn/Cu amalgam is too expensive for scale up • Replace with zinc powderReplace with zinc powder

1.4.1 Reagents1.4.1 Reagents


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• Reactions above should be avoided for scale upReactions above should be avoided for scale up• Palladium chloride and pyridinium chlorochromate are both Palladium chloride and pyridinium chlorochromate are both

carcinogeniccarcinogenic• Synthetic route would be rejected by regulatory authorities if Synthetic route would be rejected by regulatory authorities if

carcinogenic reagents are used near the end of the synthetic routecarcinogenic reagents are used near the end of the synthetic route

Examples:Examples:

N

O

PdCl2X

N

X

ROH

N

H

CrO3Cl

R CO

H

1.4 Scaling up a reaction1.4 Scaling up a reaction1.4.1 Reagents1.4.1 Reagents

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• m-Chloroperbenzoic acid is preferred over cheaper peroxide reagents m-Chloroperbenzoic acid is preferred over cheaper peroxide reagents for the Baeyer-Villiger oxidation since mcpba has a higher for the Baeyer-Villiger oxidation since mcpba has a higher decomposition temperature and is safer to usedecomposition temperature and is safer to use

Choice may need to be made between cost and safetyChoice may need to be made between cost and safety

CCH3

O OOH

O

Cl CO

O

CH3

Example:Example:

1.4 Scaling up a reaction1.4 Scaling up a reaction1.4.1 Reagents1.4.1 Reagents

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• Starting materials should be cheap and readily availableStarting materials should be cheap and readily available• Hazards of starting materials and intermediates must be Hazards of starting materials and intermediates must be

considered (e.g. diazonium salts are explosive and best avoided)considered (e.g. diazonium salts are explosive and best avoided)• May have to alter synthesis to avoid hazardous intermediatesMay have to alter synthesis to avoid hazardous intermediates

1.4.2 Reactants and intermediates1.4.2 Reactants and intermediates


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• Solvents must not be excessively flammable or toxicSolvents must not be excessively flammable or toxic• Many solvents used in research labs are unsuitable for scale up Many solvents used in research labs are unsuitable for scale up

due to flammability, cost, toxicity etc. (e.g. diethyl ether, due to flammability, cost, toxicity etc. (e.g. diethyl ether, chloroform, dioxane, benzene, hexamethylphosphoric triamide)chloroform, dioxane, benzene, hexamethylphosphoric triamide)

• Concentrations used in the research lab are relatively diluteConcentrations used in the research lab are relatively dilute• The concentration of reaction is normally increased during The concentration of reaction is normally increased during

scale up to avoid large volumes of solvent (solvent:solute ratio scale up to avoid large volumes of solvent (solvent:solute ratio 5:1 or less) 5:1 or less)

• Increased concentrations means less solvent, less hazards, Increased concentrations means less solvent, less hazards, greater economy and increased reaction ratesgreater economy and increased reaction rates

• Changing solvent can affect outcome or yieldChanging solvent can affect outcome or yield• Not feasible to purify solvents on production scaleNot feasible to purify solvents on production scale• Need to consider solvent properties when choosing solventNeed to consider solvent properties when choosing solvent

1.4.3 Solvents1.4.3 Solvents1.4 Scaling up a reaction1.4 Scaling up a reaction

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• Ignition temperature - temperature at which solvent ignitesIgnition temperature - temperature at which solvent ignites• Flash point - temperature at which vapours of the solvent Flash point - temperature at which vapours of the solvent

ignite in the presence of an ignition source (spark or flame)ignite in the presence of an ignition source (spark or flame)• Vapour pressure - measure of a solvent’s volatilityVapour pressure - measure of a solvent’s volatility• Vapour density - measure of whether vapours of the solvent Vapour density - measure of whether vapours of the solvent

rise or creep along the floorrise or creep along the floor

1.4.3.1 Properties of solvents1.4.3.1 Properties of solvents

1.4 Scaling up a reaction1.4 Scaling up a reaction1.4.3 Solvents1.4.3 Solvents

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• Solvents which are flammable at a low solvent/air mixture and Solvents which are flammable at a low solvent/air mixture and over a wide range of solvent/air mixtures (e.g. diethyl ether has over a wide range of solvent/air mixtures (e.g. diethyl ether has a flammable solvent/air range of 2-36%, is heavier than air and a flammable solvent/air range of 2-36%, is heavier than air and can creep along plant floors to ignite on hot pipes.can creep along plant floors to ignite on hot pipes.

• Solvents with a flash point less than -18Solvents with a flash point less than -18ooC (e.g. diethyl ether and C (e.g. diethyl ether and carbon disulphide).carbon disulphide).

1.4.3.2 Hazardous solvents1.4.3.2 Hazardous solvents


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• Dimethoxyethane for diethyl ether Dimethoxyethane for diethyl ether • (less flammable, higher b.pt. and higher heat capacity)(less flammable, higher b.pt. and higher heat capacity)• t-Butyl methyl ether for diethyl ether t-Butyl methyl ether for diethyl ether • (cheaper, safer and does not form peroxides)(cheaper, safer and does not form peroxides)• Heptane for pentane and hexane (less flammable)Heptane for pentane and hexane (less flammable)• Ethyl acetate for chlorinated solvents (less toxic)Ethyl acetate for chlorinated solvents (less toxic)• Toluene for benzene (less carcinogenic)Toluene for benzene (less carcinogenic)• Xylene for benzene (less carcinogenic)Xylene for benzene (less carcinogenic)• Tetrahydrofuran for dioxane (less carcinogenic)Tetrahydrofuran for dioxane (less carcinogenic)

1.4.3.3 Alternative solvents for common research solvents1.4.3.3 Alternative solvents for common research solvents


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•Reactions producing hazardous side products are unsuitable for Reactions producing hazardous side products are unsuitable for scale up.scale up.•May need to consider different reagentsMay need to consider different reagents

•Preparation of a phosphonate produces methyl chloride (gaseous, toxic and an Preparation of a phosphonate produces methyl chloride (gaseous, toxic and an alkylating agent. Trimethyl phosphite also stinksalkylating agent. Trimethyl phosphite also stinks•Sodium dimethyl phosphonate is used instead since it results in the formation of Sodium dimethyl phosphonate is used instead since it results in the formation of non-toxic NaClnon-toxic NaCl

1.4.4 SIDE PRODUCTS1.4.4 SIDE PRODUCTS

RCl

RP

O

OMe

OMe

P(OMe)3+ CH3Cl

RCl

RP

O

OMe

OMe

NaH

HPO(OMe)2

+ NaCl

ExampleExample


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1.4.5 TEMPERATURE1.4.5 TEMPERATURE

Must be practical for reaction vessels in the production plantMust be practical for reaction vessels in the production plant


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• Certain chemicals can sometimes be added at a catalytic level to Certain chemicals can sometimes be added at a catalytic level to promote reactions on large scalepromote reactions on large scale

• May remove impurities in commercial solvents and reagentsMay remove impurities in commercial solvents and reagents

Example 1Example 1• RedAl used as a promoter in cyclopropanation reaction with RedAl used as a promoter in cyclopropanation reaction with

zinczinc• Removes zinc oxides from the surface of the zincRemoves zinc oxides from the surface of the zinc• Removes water from the solventRemoves water from the solvent• Removes peroxides from the solventRemoves peroxides from the solventExample 2Example 2• Methyl magnesium iodide is used as a promoter for the Methyl magnesium iodide is used as a promoter for the

Grignard reactionGrignard reaction

1.4.6 PROMOTERS1.4.6 PROMOTERS


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Some experimental procedures carried out on small scale may be Some experimental procedures carried out on small scale may be impractical on large scaleimpractical on large scale

Examples:Examples:Scraping solids out of flasksScraping solids out of flasksConcentrating solutions to drynessConcentrating solutions to drynessRotary evaporatorsRotary evaporatorsVacuum ovens to dry oilsVacuum ovens to dry oilsChromatography for purificationChromatography for purificationDrying agents (e.g. sodium sulphate)Drying agents (e.g. sodium sulphate)Addition of reagents within short time spansAddition of reagents within short time spansUse of separating funnels for washing and extractingUse of separating funnels for washing and extracting

1.4.7 EXPERIMENTAL PROCEDURES1.4.7 EXPERIMENTAL PROCEDURES


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• Drying organic solutions Drying organic solutions - add a suitable solvent and azeotrope off the water- add a suitable solvent and azeotrope off the water- extract with brine- extract with brine

• Concentrating solutionsConcentrating solutions- carried out under normal distillation conditions- carried out under normal distillation conditions

• PurificationPurification- crystallisation preferred- crystallisation preferred

• Washing and extracting solutionsWashing and extracting solutions- stirring solvent phases in large reaction vessels- stirring solvent phases in large reaction vessels- countercurrent extraction- countercurrent extraction

Some alternative procedures suitable for large scaleSome alternative procedures suitable for large scale1.4.7 EXPERIMENTAL PROCEDURES1.4.7 EXPERIMENTAL PROCEDURES


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May play an important role in the outcome and yieldMay play an important role in the outcome and yieldParameters involvedParameters involved

- stirring efficiency- stirring efficiency- surface area to volume ratio of reactor vessel- surface area to volume ratio of reactor vessel- rate of heat transfer- rate of heat transfer- temperature gradient between the centre of the reactor - temperature gradient between the centre of the reactor

and the walls and the walls

1.4.8 PHYSICAL PARAMETERS1.4.8 PHYSICAL PARAMETERS


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DEFINITIONDEFINITIONDevelopment of the overall synthetic route to make it suitable for Development of the overall synthetic route to make it suitable for the production site and can produce batches of product in ton the production site and can produce batches of product in ton quantities with consistent yield and purityquantities with consistent yield and purity

PRIORITIESPRIORITIES• Minimising the number of reaction stepsMinimising the number of reaction steps• The use of convergent synthesesThe use of convergent syntheses• Minimising the number of operationsMinimising the number of operations• Integration of the overall reaction schemeIntegration of the overall reaction scheme• Safety - chemical hazardsSafety - chemical hazards• Safety - reaction hazardsSafety - reaction hazards• Minimising the number of purification stepsMinimising the number of purification steps• Environmental issuesEnvironmental issues• CostCost

1.5 PROCESS DEVELOPMENT1.5 PROCESS DEVELOPMENT

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1.5.1 NUMBER OF REACTION STEPS1.5.1 NUMBER OF REACTION STEPS

Minimising the number of reaction steps may increase the overall Minimising the number of reaction steps may increase the overall yieldyield

Requires a good understanding of synthetic organic chemistryRequires a good understanding of synthetic organic chemistry


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• Product synthesised in two halves then linkedProduct synthesised in two halves then linked• Preferable to linear synthesisPreferable to linear synthesis• Higher yieldsHigher yields

R S T U V

M N O P QK

L

CONVERGENT SYNTHESIS

A B C D E F G H I J KLINEAR SYNTHESIS

Overall yield =10.7% assuming an 80% yield per reactionOverall yield =10.7% assuming an 80% yield per reaction

Overall yield = 26.2% from L assuming an 80% yield per reaction Overall yield = 26.2% from L assuming an 80% yield per reaction Overall yield from R = 32.8%Overall yield from R = 32.8%

1.5 PROCESS DEVELOPMENT1.5 PROCESS DEVELOPMENT1.5.2 CONVERGENT SYNTHESES1.5.2 CONVERGENT SYNTHESES

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• Minimise the number of operations to increase the overall yieldMinimise the number of operations to increase the overall yield• Avoid isolation and purification of the intermediatesAvoid isolation and purification of the intermediates• Keep intermediates in solution for transfer from one reaction Keep intermediates in solution for transfer from one reaction

vessel to anothervessel to another• Use a solvent which is common to a series of reactions in the Use a solvent which is common to a series of reactions in the

processprocess


•The alkyl halide is not isolated, but is transferred in solution to the next The alkyl halide is not isolated, but is transferred in solution to the next reaction vessel for the Wittig reactionreaction vessel for the Wittig reaction

1.5.3 NUMBER OF OPERATIONS1.5.3 NUMBER OF OPERATIONS

AlcoholAlcohol Alkyl halideAlkyl halide Wittig reagentWittig reagentSOClSOCl22 PPhPPh33

ExampleExample

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• Assess the potential hazards of all chemicals, solvents, Assess the potential hazards of all chemicals, solvents, intermediates and residues in the process.intermediates and residues in the process.

• Introduce proper monitoring and controls to minimise the risksIntroduce proper monitoring and controls to minimise the risks

1.5 PROCESS DEVELOPMENT1.5 PROCESS DEVELOPMENT1.5.4 SAFETY - CHEMICAL HAZARDS1.5.4 SAFETY - CHEMICAL HAZARDS

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ToxicityToxicity - -• Compounds must not have an LDCompounds must not have an LD5050 less than 100mg/kg less than 100mg/kg

(teaspoon) (teaspoon) FlammabilityFlammability • Avoid high risk solvents. Avoid high risk solvents. • Medium risk solvents require precautions to avoid static Medium risk solvents require precautions to avoid static

electricityelectricityExplosivenessExplosiveness • Dust explosion test - determines whether a spark ignites a dust Dust explosion test - determines whether a spark ignites a dust

cloud of the compoundcloud of the compound• Hammer test - determines whether dropping a weight on the Hammer test - determines whether dropping a weight on the

compound produces sound or lightcompound produces sound or lightThermal instabilityThermal instability - - • Reaction process must not use temperatures higher than Reaction process must not use temperatures higher than

decomposition temperaturesdecomposition temperatures

1.5 PROCESS DEVELOPMENT1.5 PROCESS DEVELOPMENT1.5.4.1 Main hazards1.5.4.1 Main hazards

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• Assess the potential hazards of all reactions.Assess the potential hazards of all reactions.

• Carefully monitor any exothermic reactions.Carefully monitor any exothermic reactions.

• Control exothermic reactions by cooling and/or the rate at Control exothermic reactions by cooling and/or the rate at which reactants are addedwhich reactants are added

• The rate of stirring can be crucial and must be monitoredThe rate of stirring can be crucial and must be monitored

• Autocatalytic reactions are potentially dangerousAutocatalytic reactions are potentially dangerous

1.5 PROCESS DEVELOPMENT1.5 PROCESS DEVELOPMENT1.5.5 SAFETY - REACTION HAZARDS1.5.5 SAFETY - REACTION HAZARDS

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• Keep the number of purifications to a minimum to enhance the Keep the number of purifications to a minimum to enhance the overall yield overall yield

• Chromatography is often impracticalChromatography is often impractical• Ideally, purification should be carried out by crystallising only Ideally, purification should be carried out by crystallising only

the final product of the processthe final product of the process• Crystallisation conditions must be controlled to ensure Crystallisation conditions must be controlled to ensure

consistent purity, crystal form and sizeconsistent purity, crystal form and size• Crystallisation conditions must be monitored for cooling rate Crystallisation conditions must be monitored for cooling rate

and stirring rateand stirring rate• Crystals which are too large may trap solventCrystals which are too large may trap solvent• Crystals which are too fine may clog up filtersCrystals which are too fine may clog up filters• Hot filtrations prior to crystallisation must be done at least 15Hot filtrations prior to crystallisation must be done at least 15ooC C

above the crystallisation temperatureabove the crystallisation temperature

1.5 PROCESS DEVELOPMENT1.5 PROCESS DEVELOPMENT1.5.6 PURIFICATIONS1.5.6 PURIFICATIONS

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• Chemicals should be disposed of safely or recycled on Chemicals should be disposed of safely or recycled on environmental and economic groundsenvironmental and economic grounds

• Solvents should be recycled and re-usedSolvents should be recycled and re-used• Avoid mixed solvents - difficult to recycleAvoid mixed solvents - difficult to recycle• Avoid solvents with low b.pt.’s to avoid escape into the Avoid solvents with low b.pt.’s to avoid escape into the

atmosphereatmosphere• Water is the preferred solventWater is the preferred solvent• Spent reagents should be made safe before disposalSpent reagents should be made safe before disposal• Use catalysts whenever relevantUse catalysts whenever relevant• Use ‘clean’ technology whenever possible (e.g. electrochemistry, Use ‘clean’ technology whenever possible (e.g. electrochemistry,

photochemistry, ultrasound, microwaves)photochemistry, ultrasound, microwaves)

1.5 PROCESS DEVELOPMENT1.5 PROCESS DEVELOPMENT1.5.7 ENVIRONMENTAL ISSUES1.5.7 ENVIRONMENTAL ISSUES

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• Keep cost to a minimumKeep cost to a minimum

• Maximise the overall yieldMaximise the overall yield

• Minimise the cost of raw materialsMinimise the cost of raw materials

• Minimise the cost of labour and overheads by producing large Minimise the cost of labour and overheads by producing large batches on each runbatches on each run

1.5 PROCESS DEVELOPMENT1.5 PROCESS DEVELOPMENT1.5.8 COST1.5.8 COST

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DefinitionDefinitionSpecifications define a product’s properties and puritySpecifications define a product’s properties and purityAll batches must pass the predetermined specification limitsAll batches must pass the predetermined specification limitsTroubleshootingTroubleshooting Necessary if any batches fail the specificationsNecessary if any batches fail the specificationsIdentify any impurities present and their sourceIdentify any impurities present and their sourceIdentify methods of removing impurities or preventing their Identify methods of removing impurities or preventing their formationformationSources of ImpuritiesSources of ImpuritiesImpure reagents and reactantsImpure reagents and reactantsReaction conditionsReaction conditionsOrder of reagent additionOrder of reagent additionTroublesome by productsTroublesome by productsThe synthetic routeThe synthetic route

1.6 SPECIFICATIONS1.6 SPECIFICATIONS

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• Includes melting point, colour of solution, particle size, Includes melting point, colour of solution, particle size, polymorphism, pH, chemical and stereochemcial purity.polymorphism, pH, chemical and stereochemcial purity.

• Impurities present are defined and quantifiedImpurities present are defined and quantified

• Residual solvents present are defined and quantifiedResidual solvents present are defined and quantified

• Acceptable limits of impurities and solvents are definedAcceptable limits of impurities and solvents are defined

• Acceptable limits are dependent on toxicity (e.g. ethanol 2%, Acceptable limits are dependent on toxicity (e.g. ethanol 2%, methanol 0.05%)methanol 0.05%)

• Carcinogenic impurities must be absent (must not be present in Carcinogenic impurities must be absent (must not be present in final stage of synthesis)final stage of synthesis)

1.6 SPECIFICATIONS1.6 SPECIFICATIONS1.6.1 PROPERTIES AND PURITY1.6.1 PROPERTIES AND PURITY

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• Isolate, purify and identify all impurities Isolate, purify and identify all impurities (hplc, nmr, mass spectroscopy)(hplc, nmr, mass spectroscopy)

• Identify the source of any impurityIdentify the source of any impurity

• Alter the purification at the final stage, the reaction concerned Alter the purification at the final stage, the reaction concerned or the reaction conditionsor the reaction conditions

1.6 SPECIFICATIONS1.6 SPECIFICATIONS1.6.2 IMPURITIES1.6.2 IMPURITIES

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• Introduce a purification to remove any impurities at the end of Introduce a purification to remove any impurities at the end of the reaction sequence or after the offending reactionthe reaction sequence or after the offending reaction

• Methods of purification - crystallisation, distillation, Methods of purification - crystallisation, distillation, precipitation of impurity from solution, precipitation of product precipitation of impurity from solution, precipitation of product from solution from solution

1.6 SPECIFICATIONS1.6 SPECIFICATIONS1.6.3 PURIFICATIONS1.6.3 PURIFICATIONS

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• Commercially available reagents or reactants contain Commercially available reagents or reactants contain impuritiesimpurities

• Impurities introduced early on in the synthetic route may Impurities introduced early on in the synthetic route may survive the synthetic route and contaminate the productsurvive the synthetic route and contaminate the product

• An impurity at an early stage of the synthetic route may An impurity at an early stage of the synthetic route may undergo the same reactions as the starting material and undergo the same reactions as the starting material and contaminate the final productcontaminate the final product

1.6 SPECIFICATIONS1.6 SPECIFICATIONS1.6.4 IMPURE REAGENTS / REACTANTS1.6.4 IMPURE REAGENTS / REACTANTS

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Synthesis of fluvostatinSynthesis of fluvostatin

ExampleExample

F

Cl

OCl

AlCl3F

O

Cl

a) PhNHCH(CH3)2b) ZnCl2

N

H3CCH3

F

PhMeN

H

O

POCl3CH3CN

N

Ar

H3CCH3

O

HtBuOAcAc/THFnBuLi/hexaneNaH

N

Ar

H3CCH3

OH O tBu

OO

N

Ar

H3CCH3

OH O tBu

OHO

N

Ar

H3CCH3

OH O Na

OHO

Fluvostatin

NaOHEtOHH2O

a) NaBH4Et2BOCH3THF/MeOHb) H2O2

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N

Ar

H3CCH3

OH O Na

OHO

Fluvostatin

NH

NHCH2CH3

N-Ethylaniline

Impurity

N

Ar

H3COH O Na

OHO

N-Ethyl analogue of fluvostatin

Impurity

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• Vary the reaction conditions to minimise any impuritiesVary the reaction conditions to minimise any impurities(e.g. solvent, catalyst, ratio of reactants and reagents)(e.g. solvent, catalyst, ratio of reactants and reagents)

• Consider reaction kinetics and thermodynamicsConsider reaction kinetics and thermodynamicsHeating favours the thermodynamic product Heating favours the thermodynamic product Rapid addition of reactant favours the kinetic productRapid addition of reactant favours the kinetic product

• Consider sensitivity of a reagent to air and to oxidationConsider sensitivity of a reagent to air and to oxidationNN-Butyllithium oxidises in air to lithium butoxide-Butyllithium oxidises in air to lithium butoxideBenzaldehyde oxidises to benzoic acidBenzaldehyde oxidises to benzoic acidConsider using fresh reagents or a nitrogen atmosphereConsider using fresh reagents or a nitrogen atmosphere

1.6 SPECIFICATIONS1.6 SPECIFICATIONS1.6.5 REACTION CONDITIONS1.6.5 REACTION CONDITIONS

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Order in which reagents added may result in impurities Order in which reagents added may result in impurities


R O R BrH

R O

R

H Br+

Mechanism of impurity formationMechanism of impurity formation

Occurs when PBrOccurs when PBr33 is added to the alcohol but not when the alcohol is added to is added to the alcohol but not when the alcohol is added to PBrPBr33

ImpurityR OH

PBr3R Br R O

R+

ExampleExample

1.6.6 ORDER OF ADDITION1.6.6 ORDER OF ADDITION

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• By-products formed in some reactions may prove difficult to By-products formed in some reactions may prove difficult to removeremove

• Change the reaction or the reagent to get less troublesome by-Change the reaction or the reagent to get less troublesome by-products products


Example - Wittig reactionExample - Wittig reaction

R CH2BrPPh3 R CH2PPh3 Br

R' CO

H

Wittigreaction

R' CC

H

HR P Ph

O

Ph

Ph+

Triphenylphosphineoxide

By-product = triphenylphosphine oxide (requires chromatography to remove)By-product = triphenylphosphine oxide (requires chromatography to remove)

1.6.7 TROUBLESOME BY-PRODUCTS1.6.7 TROUBLESOME BY-PRODUCTS

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Horner-Emmons reaction - alternative reactionHorner-Emmons reaction - alternative reaction


By-product = Phosphonate ester (soluble in water and removed by washing)By-product = Phosphonate ester (soluble in water and removed by washing)

R CH2Br R

R' CO

H

H P

O

OMe

OMe P OMeO

MeOnBuLi

Horner-Emmonsreaction

R' CC

H

HR P OMe

O

MeO

O+

Phosphonate ester

1.6.7 TROUBLESOME BY-PRODUCTS1.6.7 TROUBLESOME BY-PRODUCTS

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1.6.8 CHANGING A SYNTHESIS1.6.8 CHANGING A SYNTHESIS1.6 SPECIFICATIONS1.6 SPECIFICATIONS

Example- Grignard synthesisExample- Grignard synthesis

CH3

MgBrC COCl

H3C

H3CH3C

CH3

C

CH3

OO C

CH3

CH3CH3

C

O

CH3

CH3CH3

+

Ester impurity

• The ester impurity is formed by oxidation of the Grignard reagent to a The ester impurity is formed by oxidation of the Grignard reagent to a phenol which then reacts with the acid chloridephenol which then reacts with the acid chloride

• Avoidable by adding Grignard reagent to the acid chloride but...Avoidable by adding Grignard reagent to the acid chloride but...• Not easy on large scale due to air sensitivity and poor solubility of the Not easy on large scale due to air sensitivity and poor solubility of the

Grignard reagentGrignard reagent

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Different routes to same productDifferent routes to same product

CH3

CCH3

CH3CH3

CCl

O

CCH3

CH3CH3

BrMgLewis acid

CH3

CO C

CH3

CH3CH3

CH3

CO

CCH3

CH3CH3

Li

Cl

CH3

CHN C

CH3

CH3CH3

CH3

CN

CCH3

CH3CH3

BrMgCH3

CO C

CH3

CH3CH3

hydrolysis

1.6.8 CHANGING A SYNTHESIS1.6.8 CHANGING A SYNTHESIS

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1.6.9 INORGANIC IMPURITIES1.6.9 INORGANIC IMPURITIES1.6 SPECIFICATIONS1.6 SPECIFICATIONS

• The final product must be checked for inorganic impurities (e.g. The final product must be checked for inorganic impurities (e.g. metal salts)metal salts)

• Deionised water may need to be used if the desired compounds Deionised water may need to be used if the desired compounds are metal ion chelators or are isolated from waterare metal ion chelators or are isolated from water

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PATENTINGPATENTING

• Carried out as soon as a potentially useful drug is identifiedCarried out as soon as a potentially useful drug is identified

• Carried out before preclinical and clinical trialsCarried out before preclinical and clinical trials

• Several years of patent protection are lost due to trialsSeveral years of patent protection are lost due to trials

• Cannot specify the exact structure that is likely to reach market Cannot specify the exact structure that is likely to reach market

• Patent a group of compounds rather than an individual structurePatent a group of compounds rather than an individual structure

2. PATENTING AND REGULATORY AFFAIRS2. PATENTING AND REGULATORY AFFAIRS

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REGULATORY AFFAIRSREGULATORY AFFAIRS

• Drug must be approved by regulatory bodiesDrug must be approved by regulatory bodies• Food and Drugs Administration (FDA)Food and Drugs Administration (FDA)• European Agency for the Evaluation of Medicinal Products European Agency for the Evaluation of Medicinal Products

(EMEA)(EMEA)

• Proper record keeping is essentialProper record keeping is essential

• GLP - Good Laboratory PracticeGLP - Good Laboratory Practice

• GMP - Good Manufacturing PracticeGMP - Good Manufacturing Practice

• GCP - Good Clinical PracticeGCP - Good Clinical Practice

2. PATENTING AND REGULATORY AFFAIRS2. PATENTING AND REGULATORY AFFAIRS

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Phase 1Phase 1• Carried out on healthy volunteersCarried out on healthy volunteers• Useful in establishing dose levelsUseful in establishing dose levels• Useful for studying pharmacokinetics, including drug metabolismUseful for studying pharmacokinetics, including drug metabolism

3. CLINICAL TRIALS3. CLINICAL TRIALS

Phase 2Phase 2• Carried out on patientsCarried out on patients• Carried out as double blind studies Carried out as double blind studies • Demonstrates whether a drug is therapeutically usefulDemonstrates whether a drug is therapeutically useful• Establishes a dosing regimeEstablishes a dosing regime• Identifies side effectsIdentifies side effects

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Phase 3Phase 3• Carried out on a larger number of patientsCarried out on a larger number of patients• Establishes statistical proof for efficacy and safetyEstablishes statistical proof for efficacy and safety

3. CLINICAL TRIALS3. CLINICAL TRIALS

Phase 4Phase 4• Continued after a drug reaches the marketContinued after a drug reaches the market• Studies long term effects when used chronicallyStudies long term effects when used chronically• Identifies unusual side effectsIdentifies unusual side effects

patrick an introduction to medicinal chemistry 3/e chapter 12 drug design & development

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