Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 12
DRUG DESIGN &
DEVELOPMENT
©1
Contents
1.
Preclinical trials
1.1. Chemical Development (2 Slides)
1.2. The Initial Synthesis (3 Slides)
1.3. Optimisation of Reactions
1.3.1.
1.3.2.
1.3.3.
1.3.4.
1.3.5.
1.3.6.
1.3.7.
1.3.8.
1.3.9.
1.3.10.
continued…
1.5. Process Development
1.5.1.
1.5.2.
1.5.3.
1.5.4.
Temperature
Pressure (2 Slides)
Reaction Time
Solvent (3 Slides)
Concentration
Catalysts (2 Slides)
Excess Reactant
Removing a Product
Methods of Addition (2
Slides)
Reactivity of Reagents &
Reactants
1.5.5.
1.5.6.
1.5.7.
1.5.8.
1.6. Specifications
1.6.1.
1.6.2.
1.6.3.
1.6.4.
1.6.5.
1.6.6.
1.6.7.
1.4. Scaling Up A Reaction
1.4.1.
1.4.2.
1.4.3.
1.4.4.
1.4.5.
1.4.6.
1.4.7.
1.4.8.
Reagents (3 Slides)
Reactants And
Intermediates
Solvents (4 Slides)
Side Products
Temperature
Promoters
Experimental Procedures (2
Slides)
Physical Para Meters
Number Of Reaction Steps
Convergent Syntheses
Number Of Operations
Safety - Chemical Hazards
1.5.4.1.
Main Hazards
Safety - Reaction Hazards
Purifications
Environmental Issues
Cost
1.6.8.
1.6.9.
2.
3.
Properties And Purity
Impurities
Purifications
Impure Reagents /
Reactants (3 Slides)
Reaction Conditions
Order Of Addition
Troublesome By-Products
(2 Slides)
Changing A Synthesis (2
Slides)
Inorganic Impurities
Patenting And Regulatory Affairs
Clinical Trials (2 Slides)
[67 slides]
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Drug design and development
Stages:
1) Identify target disease
2) Identify drug target
3) Establish testing procedures
4) Find a lead compound
5) Structure Activity Relationships (SAR)
6) Identify a pharmacophore
7) Drug design- optimising target interactions
8) Drug design - optimising pharmacokinetic properties
9) Preclinical trials
10) Chemical development and process development
11) Patenting and regulatory affairs
12) Clinical trials
Note: Stages 9-11 are usually carried out in parallel
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1. Preclinical trials
Drug Metabolism
Identification of drug metabolites in test animals
Properties of drug metabolites
Toxicology
In vivo and in vitro tests for acute and chronic
toxicity
Pharmacology
Selectivity of action at drug target
Formulation
Stability tests
Methods of delivery
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1.1 Chemical Development
Definition:
Development of a synthesis suitable for large scale
production up to 100kg.
Priorities:
• To optimise the final synthetic step and the purification procedures
• To define the product specifications
• To produce a product that consistently passes the purity
specifications
• To produce a high quality product in high yield using a synthesis
that is cheap and efficient.
• To produce a synthesis that is safe and environmentally friendly
with a minimum number of steps
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1.1 Chemical Development
Phases:
•
•
•
Synthesis of 1kg for initial preclinical testing (often a scale up of the
original synthesis)
Synthesis of 10kg for toxicological studies, formulation and initial
clinical trials
Synthesis of 100kg for clinical trials
Notes:
•
•
•
•
•
Chemical development is more than just scaling up the original
synthesis
Different reaction conditions or synthetic routes often required
Time period can be up to 5 years
Need to balance long term aims of developing a large scale
synthesis versus short term need for batches for preclinical trials
The product produced by the fully developed route must meet the
same specifications as defined at phase 1
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1.2 The initial synthesis
Origin
• The initial synthesis was designed in the research lab
Priorities of the original synthesis
• To synthesise as many different compounds as quickly as possible in
order to identify active compounds
• Yield and cost are low priorities
• usually done on small scale
Likely problems related to the original synthesis
• The use of hazardous starting materials and reagents
• Experimental procedures which are impractical on large scale
• the number of reaction steps involved
• Yield and cost
Scale up
• Original synthesis may be scaled up for the first 1 kg of product but is
then modified or altered completely for larger quantities
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1.2 The initial synthesis
The initial synthesis of fexofenadine (anti-asthmatic)
O
C Cl
R
C
O
Cl
C
Me
Me
R
C
R2NH
Me
O
R
C
C
Me
Me
Friedel Crafts
Acylation
Cl
Me
R2N
HO
R
C
Me
Me
N
Reduction
HO
Ph
•
•
•
Ph
R= Me; Terfenadine
R=CO 2H; Fexofenadine
Fexofenadine synthesised by the same route used for terfenadine
Unsatisfactory since the Friedel Crafts reaction gives the meta isomer as well
Requires chromatography to remove the meta isomer
©1
1.2 The initial synthesis
Revised synthesis of fexofenadine
OH
O
OHC
Me
O
Oxidation
C
Me
CO2Et
C
Me
Me
MgBr
CO2Et
O
O
C
Me
HO
CO2Et
C
O
1)
CO2Et
Me
Me
•
•
•
2) NaBH4
Me
Me
NH
Amberlyst
Me
Me
H
O
HO
Ph
Ph
CO2Et
N
HO
Ester
hydrolysis
Fexofenadine
Ph
Ph
More practical and efficient synthesis using easily available starting materials
No ‘awkward’ isomers are formed
No chromatography required for purification
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1.3 Optimisation of reactions
Aims:
• To optimise the yield and purity of product from each reaction
Notes:
• Maximum yield does not necessarily mean maximum purity
• May need to accept less than the maximum yield to achieve an
acceptable purity
• Need to consider cost and safety
Factors:
• Temperature, reaction time, stirring rate, pH, pressure,
catalysts, order and rate of addition of reactants and reagents,
purification procedure.
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1.3 Optimisation of reactions
1.3.1 Temperature
•
•
•
•
Optimum temperature is the temperature at which the rate of
reaction is maximised with a minimum of side reactions
Increasing the temperature increases the reaction rate
Increasing the temperature may increase side reactions and
increase impurities
Compromise is often required
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1.3 Optimisation of reactions
1.3.2 Pressure
•
•
Increased pressure (> 5 kilobar) accelerates reactions where the
transition state occupies a smaller volume than the starting
materials.
Useful if increased heating causes side reactions
Examples of reactions accelerated by pressure
• Esterifications; amine quaternisation; ester hydrolysis; Claisen
and Cope rearrangements; nucleophilic substitutions; Diels
Alder reactions
Example: Esterification of acetic acid with ethanol
• proceeds 5 times faster at 2 kbar than at 1 atm.
• proceeds 26 times faster at 4 kbar
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1.3 Optimisation of reactions
1.3.2 Pressure
Example 1:
PPh3
O
O
O
Br
•
•
•
benzene-toluene
20 oC / 15,000atm
O
PPh3
Good yield at 20oC and 15 kbar
No reaction at 20oC and 1 atmosphere
Decomposition at 80oC and 1 atmosphere
Example 2:
•
•
Hydrolysis of chiral esters using base with heating may cause
racemisation
Can be carried out at room temperature with pressure instead
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1.3 Optimisation of reactions
1.3.3 Reaction time
• Optimum reaction time is the time required to get the best yield
consistent with high purity.
• Monitor reactions to find the optimum time using tlc, gas
chromatography, IR, NMR, HPLC
• If reaction goes to completion, optimum time is often the time
required to reach completion
• If reaction reaches equilibrium, optimum time is often the time
required to reach equilibrium
• However, optimum time may not be the same as the time to reach
completion or equilibrium if side reactions take place
• Excess reaction times increase the chances of side reactions and the
formation of impurities.
• Reaction times greater than 15 hr should be avoided (costly at
production level)
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1.3 Optimisation of reactions
1.3.4 Solvent
•
•
•
Important to outcome, yield and purity
Should normally be capable of dissolving reactants and reagents
Insolubility of a product in solvent may improve yields by shifting an
equilibrium reaction to its products (but this may be a problem with
catalysts)
Example:
OH
O
H H
N
O
C
O
O
N
H H
OH
O
H3N
H2 Pd/C
O
H
O
N
H H
O
EtOH/H2O
•
•
•
Poor yield in ethanol - product precipitates and coats the catalyst
Poor yield in water - reactant poorly soluble
Quantitative yield in ethanol-water; 1:1
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1.3 Optimisation of reactions
1.3.4 Solvent
•
•
•
•
•
•
Should have a suitable boiling point if one wishes to heat the
reaction at a constant temperature (heating to reflux)
Should be compatible with the reaction being carried out
Solvents are classed as polar (EtOH, H2O, acetone) or nonpolar
(toluene, chloroform)
Polar solvents are classed as protic (EtOH, H2O) or aprotic
(DMF, DMSO)
Protic solvents are capable of H-bonding
The polarity and the H-bonding ability of the solvent may
affect the reaction
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1.3 Optimisation of reactions
1.3.4 Solvent
Example:
•
•
Protic solvents give higher rates for SN1 reactions but not for SN2
reactions - they aid departure of anion in the rate determining step
Dipolar aprotic solvents (DMSO) are better for SN2 reactions
Cl
R
•
•
•
•
NaCN
DMSO
CN
R
SN2 reaction
Solvent DMSO; reaction time 1-2 hours
Solvent aq. ethanol; reaction time 1-4 days
DMSO solvates cations but leaves anions relatively
unsolvated
Thus, the nucleophile is more reactive
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1.3 Optimisation of reactions
1.3.5 Concentration
•
High concentration (small volume of solvent) favours
increased reaction rate but may increase chance of side
reactions
•
Low concentrations (large volume of solvent) are useful for
exothermic reactions (solvent acts as a ‘heat sink’)
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1.3 Optimisation of reactions
1.3.6 Catalysts
•
•
•
Increase rate at which reactions reach equilibrium
Classed as heterogeneous or homogeneous
Choice of catalyst can influence type of product obtained and
yield
Example:
H
H2 Pd/C
R
C
C
R
R
H
C
R
C
C
R
R
C
R
Poisoned
catalyst
R
H
H
H2 Pd/CaCO 3
C
H
C
H
©1
1.3 Optimisation of reactions
1.3.6 Catalysts
Example:
O
R
Cl
C
R
Lewis acid
R
R
C
O
Vary Lewis acid catalysts (e.g. AlCl3 or ZnCl2) to optimise yield and
purity
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1.3 Optimisation of reactions
1.3.7 Excess reactant
•
•
•
Shifts equilibrium to products if reaction is thermodynamically
controlled
Excess reactant must be cheap, readily available and easily
separated from product
May also affect outcome of reaction
Example:
O
H2N
Ph
O
O
O
Ph
NH2
C
O
•
H
N
+
NH2
H
N
C
C
N
H
O
Excess diamine is used to increase the proportion of mono-acylated product
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1.3 Optimisation of reactions
1.3.8 Removing a product
•
•
Removing a product shifts the equilibrium to products if the
reaction is in equilibrium
Can remove a product by precipitation, distillation or
crystallisation
Example:
O
+
R
R
OH
HO
Ptsa catalyst
O
O
R
R
+
H 2O
Removing water by distillation shifts equilibrium to right
©1
1.3 Optimisation of reactions
1.3.9 Methods of addition
•
Adding one reactant or reagent slowly to another helps to
control the temperature of fast exothermic reactions
•
Stirring rates may be crucial to prevent localised regions of
high concentration
+
•
Dilution of reactant or reagent in solvent before addition helps
to prevent localised areas of high concentration
•
Order of addition may influence the outcome and yield
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1.3 Optimisation of reactions
1.3.9 Methods of addition
Example:
Ar
Ar
Ar
1) nBuLi
2) RCHO
OMe
N
N
P
O
+
R
N
R
OMe
impurity
•
•
Impurity is formed when butyl lithium is added to the
phosphonate (the phosphonate anion reacts with unreacted
phosphonate)
No impurity is formed if the phosphonate is added to butyl lithium
©1
1.3 Optimisation of reactions
1.3.10 Reactivity of reagents and reactants
Less reactive reagents may affect the outcome of the reaction
Example:
O
Cl
H2N
O
NH2
C
O
•
•
H
N
H
N
+
NH2
C
C
N
H
O
A 1:1 mixture of mono and diacylated products is obtained even when
benzyl chloride is added to the diamine
Using less reactive benzoic anhydride gives a ratio of mono to diacylated
product of 1.86:0.14
©1
1.4 Scaling up a reaction
Priorities
Cost, safety and practicality
Factors to consider
Reagents, reactants and intermediates, solvents, side products,
temperature, promoters, procedures, physical parameters
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1.4 Scaling up a reaction
1.4.1 Reagents
•
•
•
•
Reagents used in the initial synthesis are often unsuitable due to
cost or hazards.
Hazardous by products may be formed from certain reagents (e.g.
mercuric acetate from mercury)
Reagents may be unsuitable on environmental grounds (e.g. smell)
Reagents may be unsuitable to handle on large scale (e.g.
hygroscopic or lachrymatory compounds)
Example:
H
H
Zn/Cu
Et2O
CH2I2
H
R
R
•
•
H
R
R
Zn/Cu amalgam is too expensive for scale up
Replace with zinc powder
©1
1.4 Scaling up a reaction
1.4.1 Reagents
Examples:
X
X
PdCl2
N
N
O
CrO3Cl
N
OH
R
O
H
R
C
H
•
•
•
Reactions above should be avoided for scale up
Palladium chloride and pyridinium chlorochromate are both
carcinogenic
Synthetic route would be rejected by regulatory authorities if
carcinogenic reagents are used near the end of the synthetic route
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1.4 Scaling up a reaction
1.4.1 Reagents
Choice may need to be made between cost and safety
Example:
O
O
O
O
C
CH3
•
OH
Cl
C
O
CH3
m-Chloroperbenzoic acid is preferred over cheaper peroxide reagents
for the Baeyer-Villiger oxidation since mcpba has a higher
decomposition temperature and is safer to use
©1
1.4 Scaling up a reaction
1.4.2 Reactants and intermediates
•
Starting materials should be cheap and readily available
•
Hazards of starting materials and intermediates must be
considered (e.g. diazonium salts are explosive and best avoided)
•
May have to alter synthesis to avoid hazardous intermediates
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1.4 Scaling up a reaction
1.4.3 Solvents
• Solvents must not be excessively flammable or toxic
• Many solvents used in research labs are unsuitable for scale up
due to flammability, cost, toxicity etc. (e.g. diethyl ether,
chloroform, dioxane, benzene, hexamethylphosphoric triamide)
• Concentrations used in the research lab are relatively dilute
• The concentration of reaction is normally increased during scale
up to avoid large volumes of solvent (solvent:solute ratio 5:1 or
less)
• Increased concentrations means less solvent, less hazards,
greater economy and increased reaction rates
• Changing solvent can affect outcome or yield
• Not feasible to purify solvents on production scale
• Need to consider solvent properties when choosing solvent
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1.4 Scaling up a reaction
1.4.3 Solvents
1.4.3.1 Properties of solvents
•
Ignition temperature - temperature at which solvent ignites
•
Flash point - temperature at which vapours of the solvent
ignite in the presence of an ignition source (spark or flame)
•
Vapour pressure - measure of a solvent’s volatility
•
Vapour density - measure of whether vapours of the solvent
rise or creep along the floor
©1
1.4 Scaling up a reaction
1.4.3 Solvents
1.4.3.2 Hazardous solvents
•
Solvents which are flammable at a low solvent/air mixture and
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
can creep along plant floors to ignite on hot pipes.
•
Solvents with a flash point less than -18oC (e.g. diethyl ether and
carbon disulphide).
©1
1.4 Scaling up a reaction
1.4.3 Solvents
1.4.3.3 Alternative solvents for common research solvents
•
Dimethoxyethane for diethyl ether
•
(less flammable, higher b.pt. and higher heat capacity)
•
t-Butyl methyl ether for diethyl ether
•
(cheaper, safer and does not form peroxides)
•
Heptane for pentane and hexane (less flammable)
•
Ethyl acetate for chlorinated solvents (less toxic)
•
Toluene for benzene (less carcinogenic)
•
Xylene for benzene (less carcinogenic)
•
Tetrahydrofuran for dioxane (less carcinogenic)
©1
1.4 Scaling up a reaction
1.4.4 SIDE PRODUCTS
•Reactions producing hazardous side products are unsuitable for
scale up.
•May need to consider different reagents
Example
P(OMe)3
R
R
OMe
P
Cl
O
NaH
R
Cl
+ CH3Cl
OMe
R
OMe
+ NaCl
P
HPO(OMe)2
O
OMe
•Preparation of a phosphonate produces methyl chloride (gaseous, toxic and an
alkylating agent. Trimethyl phosphite also stinks
•Sodium dimethyl phosphonate is used instead since it results in the formation of
non-toxic NaCl
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1.4 Scaling up a reaction
1.4.5 TEMPERATURE
Must be practical for reaction vessels in the production plant
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1.4 Scaling up a reaction
1.4.6 PROMOTERS
•
•
Certain chemicals can sometimes be added at a catalytic level to
promote reactions on large scale
May remove impurities in commercial solvents and reagents
Example 1
• RedAl used as a promoter in cyclopropanation reaction with
zinc
• Removes zinc oxides from the surface of the zinc
• Removes water from the solvent
• Removes peroxides from the solvent
Example 2
• Methyl magnesium iodide is used as a promoter for the
Grignard reaction
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1.4 Scaling up a reaction
1.4.7 EXPERIMENTAL PROCEDURES
Some experimental procedures carried out on small scale may be
impractical on large scale
Examples:
Scraping solids out of flasks
Concentrating solutions to dryness
Rotary evaporators
Vacuum ovens to dry oils
Chromatography for purification
Drying agents (e.g. sodium sulphate)
Addition of reagents within short time spans
Use of separating funnels for washing and extracting
©1
1.4 Scaling up a reaction
1.4.7 EXPERIMENTAL PROCEDURES
Some alternative procedures suitable for large scale
•
Drying organic solutions
- add a suitable solvent and azeotrope off the water
- extract with brine
•
Concentrating solutions
- carried out under normal distillation conditions
•
Purification
- crystallisation preferred
•
Washing and extracting solutions
- stirring solvent phases in large reaction vessels
- countercurrent extraction
©1
1.4 Scaling up a reaction
1.4.8 PHYSICAL PARA METERS
May play an important role in the outcome and yield
Parameters involved
- stirring efficiency
- surface area to volume ratio of reactor vessel
- rate of heat transfer
- temperature gradient between the centre of the reactor
and the walls
©1
1.5 PROCESS DEVELOPMENT
DEFINITION
Development of the overall synthetic route to make it suitable for
the production site and can produce batches of product in ton
quantities with consistent yield and purity
PRIORITIES
• Minimising the number of reaction steps
• The use of convergent syntheses
• Minimising the number of operations
• Integration of the overall reaction scheme
• Safety - chemical hazards
• Safety - reaction hazards
• Minimising the number of purification steps
• Environmental issues
• Cost
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1.5 PROCESS DEVELOPMENT
1.5.1 NUMBER OF REACTION STEPS
Minimising the number of reaction steps may increase the overall
yield
Requires a good understanding of synthetic organic chemistry
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1.5 PROCESS DEVELOPMENT
1.5.2 CONVERGENT SYNTHESES
•
•
•
Product synthesised in two halves then linked
Preferable to linear synthesis
Higher yields
LINEAR SYNTHESIS
A
B
C
D
E
F
G
H
I
J
K
Overall yield =10.7% assuming an 80% yield per reaction
CONVERGENT SYNT HESIS
L
M
N
O
P
Q
K
R
S
T
U
V
Overall yield = 26.2% from L assuming an 80% yield per reaction
Overall yield from R = 32.8%
©
1
1.5 PROCESS DEVELOPMENT
1.5.3 NUMBER OF OPERATIONS
•
•
•
•
Minimise the number of operations to increase the overall yield
Avoid isolation and purification of the intermediates
Keep intermediates in solution for transfer from one reaction
vessel to another
Use a solvent which is common to a series of reactions in the
process
Example
Alcohol
SOCl2
Alkyl halide
PPh3
Wittig reagent
•The alkyl halide is not isolated, but is transferred in solution to the next
reaction vessel for the Wittig reaction
©1
1.5 PROCESS DEVELOPMENT
1.5.4 SAFETY - CHEMICAL HAZARDS
•
Assess the potential hazards of all chemicals, solvents,
intermediates and residues in the process.
•
Introduce proper monitoring and controls to minimise the risks
©1
1.5 PROCESS DEVELOPMENT
1.5.4.1 Main hazards
Toxicity • Compounds must not have an LD50 less than 100mg/kg
(teaspoon)
Flammability
• Avoid high risk solvents.
• Medium risk solvents require precautions to avoid static
electricity
Explosiveness
• Dust explosion test - determines whether a spark ignites a dust
cloud of the compound
• Hammer test - determines whether dropping a weight on the
compound produces sound or light
Thermal instability • Reaction process must not use temperatures higher than
decomposition temperatures
©1
1.5 PROCESS DEVELOPMENT
1.5.5 SAFETY - REACTION HAZARDS
•
Assess the potential hazards of all reactions.
•
Carefully monitor any exothermic reactions.
•
Control exothermic reactions by cooling and/or the rate at
which reactants are added
•
The rate of stirring can be crucial and must be monitored
•
Autocatalytic reactions are potentially dangerous
©1
1.5 PROCESS DEVELOPMENT
1.5.6 PURIFICATIONS
•
•
•
•
•
•
•
•
Keep the number of purifications to a minimum to enhance the
overall yield
Chromatography is often impractical
Ideally, purification should be carried out by crystallising only
the final product of the process
Crystallisation conditions must be controlled to ensure
consistent purity, crystal form and size
Crystallisation conditions must be monitored for cooling rate
and stirring rate
Crystals which are too large may trap solvent
Crystals which are too fine may clog up filters
Hot filtrations prior to crystallisation must be done at least 15oC
above the crystallisation temperature
©1
1.5 PROCESS DEVELOPMENT
1.5.7 ENVIRONMENTAL ISSUES
•
•
•
•
•
•
•
•
Chemicals should be disposed of safely or recycled on
environmental and economic grounds
Solvents should be recycled and re-used
Avoid mixed solvents - difficult to recycle
Avoid solvents with low b.pt.’s to avoid escape into the
atmosphere
Water is the preferred solvent
Spent reagents should be made safe before disposal
Use catalysts whenever relevant
Use ‘clean’ technology whenever possible (e.g. electrochemistry,
photochemistry, ultrasound, microwaves)
©1
1.5 PROCESS DEVELOPMENT
1.5.8 COST
•
Keep cost to a minimum
•
Maximise the overall yield
•
Minimise the cost of raw materials
•
Minimise the cost of labour and overheads by producing large
batches on each run
©1
1.6 SPECIFICATIONS
Definition
Specifications define a product’s properties and purity
All batches must pass the predetermined specification limits
Troubleshooting
Necessary if any batches fail the specifications
Identify any impurities present and their source
Identify methods of removing impurities or preventing their
formation
Sources of Impurities
Impure reagents and reactants
Reaction conditions
Order of reagent addition
Troublesome by products
The synthetic route
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1.6 SPECIFICATIONS
1.6.1 PROPERTIES AND PURITY
•
Includes melting point, colour of solution, particle size,
polymorphism, pH, chemical and stereochemcial purity.
•
Impurities present are defined and quantified
•
Residual solvents present are defined and quantified
•
Acceptable limits of impurities and solvents are defined
•
Acceptable limits are dependent on toxicity (e.g. ethanol 2%,
methanol 0.05%)
•
Carcinogenic impurities must be absent (must not be present in
final stage of synthesis)
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1.6 SPECIFICATIONS
1.6.2 IMPURITIES
•
Isolate, purify and identify all impurities
(hplc, nmr, mass spectroscopy)
•
Identify the source of any impurity
•
Alter the purification at the final stage, the reaction concerned
or the reaction conditions
©1
1.6 SPECIFICATIONS
1.6.3 PURIFICATIONS
•
Introduce a purification to remove any impurities at the end of
the reaction sequence or after the offending reaction
•
Methods of purification - crystallisation, distillation,
precipitation of impurity from solution, precipitation of product
from solution
©1
1.6 SPECIFICATIONS
1.6.4 IMPURE REAGENTS / REACTANTS
•
Commercially available reagents or reactants contain impurities
•
Impurities introduced early on in the synthetic route may
survive the synthetic route and contaminate the product
•
An impurity at an early stage of the synthetic route may
undergo the same reactions as the starting material and
contaminate the final product
©1
1.6 SPECIFICATIONS
Example
F
Ar
F
F
P hMe N
AlCl3
Cl
a) PhNHCH(CH3)2
b) ZnCl2
Cl
N
POCl3
CH3CN
Cl
H3C
N
H3C
a) NaBH4
Et2BOCH 3
THF/MeOH
b) H2O 2
Ar
O
NaOH
EtOH
H2O
Ar
OH
O
N
N
CH3
OH
O tBu
H3C
CH3
CH3
O
tBuOAcAc/THF
nBuLi/hexane
NaH
CH3
O
H3C
H
H
O
O
O
OH
O tBu
Ar
OH
O
N
H3C
CH3
OH
Fluvostatin
Synthesis of fluvostatin
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O Na
1.6 SPECIFICATIONS
Ar
OH
NH
O
N
CH3
H3C
OH
O Na
Fluvostatin
Ar
NHCH 2CH 3
OH
Impurity
O
N
N-Ethylaniline
Impurity
OH
H3C
O Na
N-Ethyl analogue of fluvostatin
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1.6 SPECIFICATIONS
1.6.5 REACTION CONDITIONS
•
Vary the reaction conditions to minimise any impurities
(e.g. solvent, catalyst, ratio of reactants and reagents)
•
Consider reaction kinetics and thermodynamics
Heating favours the thermodynamic product
Rapid addition of reactant favours the kinetic product
•
Consider sensitivity of a reagent to air and to oxidation
N-Butyllithium oxidises in air to lithium butoxide
Benzaldehyde oxidises to benzoic acid
Consider using fresh reagents or a nitrogen atmosphere
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1.6 SPECIFICATIONS
1.6.6 ORDER OF ADDITION
Order in which reagents added may result in impurities
Example
R
OH
PBr3
R
R
+
Br
R
O
Impurity
Mechanism of impurity formation
H
R
O
R
R
Br
R
O
+
H
Br
Occurs when PBr3 is added to the alcohol but not when the alcohol is added to
PBr3
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1.6 SPECIFICATIONS
1.6.7 TROUBLESOME BY-PRODUCTS
• By-products formed in some reactions may prove difficult to
remove
• Change the reaction or the reagent to get less troublesome byproducts
Example - Wittig reaction
R
CH2Br
PPh3
R
CH2PPh 3
Br
H
O
C
R'
O
R'
Wittig
reaction
C
H
R
Ph
P
Ph
+
C
H
Ph
T riphenylphosphine
oxide
By-product = triphenylphosphine oxide (requires chromatography to remove)
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1.6 SPECIFICATIONS
1.6.7 TROUBLESOME BY-PRODUCTS
Horner-Emmons reaction - alternative reaction
O
H
P
OMe
OMe
R
CH2Br
MeO
MeO
P
R
O
H
nBuLi
C
R'
O
R'
C
Horner-Emmons
reaction
O
C
H
R
+
MeO
P
OMe
O
Phosphonate ester
H
By-product = Phosphonate ester (soluble in water and removed by washing)
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1.6 SPECIFICATIONS
1.6.8 CHANGING A SYNTHESIS
Example- Grignard synthesis
CH3
CH3
CH3
+
H3C
MgBr
H3C
H3C
C
COCl
C
O
C
CH3
CH3
CH3
CH3
CH3
C
CH3
O
O
Ester impurity
•
•
•
The ester impurity is formed by oxidation of the Grignard reagent to a
phenol which then reacts with the acid chloride
Avoidable by adding Grignard reagent to the acid chloride but...
Not easy on large scale due to air sensitivity and poor solubility of the
Grignard reagent
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1.6 SPECIFICATIONS
1.6.8 CHANGING A SYNTHESIS
Different routes to same product
Li
CH 3
C
CH3
O
CH3
CH 3
C
CH 3
Cl
C
CH3
CH 3
CH 3
CH 3
BrMg
CH 3
C
Lewis acid
CH 3
O
C
CH 3
O
Cl
CH3
C
C
CH3
CH3
CH3
BrMg
C
CH3
CH 3
CH3
CH 3
CH 3
CN
hydrolysis
HN
C
C
CH3
CH3
CH3
O
C
C
CH3
CH3
CH3
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1.6 SPECIFICATIONS
1.6.9 INORGANIC IMPURITIES
•
The final product must be checked for inorganic impurities (e.g.
metal salts)
•
Deionised water may need to be used if the desired compounds
are metal ion chelators or are isolated from water
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2. PATENTING AND REGULATORY AFFAIRS
PATENTING
•
Carried out as soon as a potentially useful drug is identified
•
Carried out before preclinical and clinical trials
•
Several years of patent protection are lost due to trials
•
Cannot specify the exact structure that is likely to reach market
•
Patent a group of compounds rather than an individual structure
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2. PATENTING AND REGULATORY AFFAIRS
REGULATORY AFFAIRS
•
•
•
Drug must be approved by regulatory bodies
Food and Drugs Administration (FDA)
European Agency for the Evaluation of Medicinal Products (EMEA)
•
Proper record keeping is essential
•
GLP - Good Laboratory Practice
•
GMP - Good Manufacturing Practice
•
GCP - Good Clinical Practice
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3. CLINICAL TRIALS
Phase 1
• Carried out on healthy volunteers
• Useful in establishing dose levels
• Useful for studying pharmacokinetics, including drug metabolism
Phase 2
• Carried out on patients
• Carried out as double blind studies
• Demonstrates whether a drug is therapeutically useful
• Establishes a dosing regime
• Identifies side effects
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3. CLINICAL TRIALS
Phase 3
• Carried out on a larger number of patients
• Establishes statistical proof for efficacy and safety
Phase 4
• Continued after a drug reaches the market
• Studies long term effects when used chronically
• Identifies unusual side effects
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