Process Development

Question 1

Telescoping

Answer 1

Product from a chemical reaction is not isolated and purified –instead it is used directly in the next reaction.

Question 2

Telescoping

Advantages and disadvantages

Answer 2

Avoids isolation of unstable or toxic compounds, or compounds with undesirable physical characteristics (oily, non-crystalline compounds)–Can only be used for reactions that generate minimal impurities, and reach completion (no unreacted starting materials)–Isolation and purification steps are often most difficult/time consuming steps –telescoping highly desirable where possible.

Question 3

Linear routes

Advantages and disadvantages

Answer 3

Often utilised as the starting point for process development-gives option for late-stage diversification critical to medicinal chemistry.•Reduced overall yield -most importantly low yielding steps near the end of the route need to be identified (key focus early development is speed of delivery).•Simplified manufacturing process –no holds are required, BUT large margin needed in planning•Unanticipated low yield = lengthy resynthesis.

Question 4

Convergent Routes

Advantages and disadvantages

Answer 4

Greater efficiency•Scheduling and stability may be problematic•Unanticipated low yield accommodated by short synthesis

Question 5

Purification Techniques:

Answer 5

Crystallisation

Chromatography

Question 6

Crystallisation

Answer 6

Main purification method used for intermediate or API purification –scalable•Crystalline target highly desirable due to manufacturing process and stability of product•Very high purities attainable (99.9%)•Potential to improve d.e. / e.e. of reactions•Polymorphism –needs to be considered

Question 7

Chromatography

Answer 7

Requires large quantities of solvent, silica•Requires days on scale•Performance decreases with scale (non-plug flow, channeling)
Now, use of automated chromatography systems (plant scale) reduces the inefficiency of this technique•Enantiomericseparations by chromatography using chiral columns –extensively used in commercial production.

Question 8

Green Chemistry define

Answer 8

Used to support and reinforce movement towards greener and sustainable chemistry

Question 9

Green Chemistry metrics

Answer 9

1.Atom Economy2.Environmental Factor3.Reaction Mass Efficiency4.Process Mass Intensity

Question 10

Atom economy Definition:

Answer 10

MWtof desired product /MWtof all products x 100%

Easy to calculate from reaction scheme-Does not take into account reaction yield, solvent usage or other reagents used in the work-up

Question 11

E-factor:

environmental

Answer 11

defined as ratio of waste over product

Question 12

Reaction mass efficiency

•Defined as:=

Answer 12

mass of desired product/ mass of all reactants percentage

Question 13

Process Mass Intensity•Defined as:

Answer 13

Mass of all materials used to produce product/ Mass of product (x 100%)

Question 14

Biocatalysis

Answer 14

Catalyst is an enzyme derived from renewable resources that is biodegradable.•

Question 15

Biocatalysis

Advantages and disadvantages

Answer 15

Catalysis generally proceeds with high chemo-, regio-and stereoselectivity. Often a clean reaction•Avoids the need for protection and deprotectionsteps.•Reactions often carried out in water with mild conditions (temperature, pH and pressure).•Purification is simplified•Catalyst may be recycled•Very favourable for large-scale work.

Question 16

Around 54% of APIs are chiral with two stereogeniccentres (on average) –of these around 50% are racemic mixtures
.•Enantiomers have ______physical and chemical properties in an achiral environment –biological systems are chiral, therefore each enantiomer can behave differently in vivo.
•Enantiomers of chiral drugs must considered as ______drugs with different properties UNLESS proven otherwise (move towards enantiopuredrugs).

Answer 16

identical

separate

Question 17

Chirality installation
•Chirality is derived from purchased starting material for 55% of chiral APIs –desire to introduce chirality early into reaction schemes.

Answer 17

–Chiral pool approach ( Cheap, enantiopure•Similarity to drug?•Atom efficiency)

In-house generation of chirality (–resolution (62% of APIs): classical salt formations accounts for 2/3 of resolution technique other methods include dynamic kinetic, enzymatic and chromatographic resolutions–asymmetric synthesis (~20% of APIs) -catalytic in nature.)

Question 18

Route design and selection
•Process chemistry involves investigation of multiple synthetic routes to a single API target
–All routes must be evaluated how? to find the most efficient process

Answer 18

the SELECTcriteria is routinely used for route evaluation: Safety, Environmental, Legal, Economics, Control and Throughput.