Aims of Chemical Development

Development and Optimization

the investigative approach

PhD

IN INDUSTRIAL CHEMISTRY AND CHEMICAL ENGINEERING (CII)

Aims of Chemical Development

• Produce a cheap product (short route, high yields)

• Simplify process

• Discover robust and safe process

• Demonstrate process works well on plant

• Use available plant efficiently But Also

•

Minimize effluent

•

Understand the chemistry and the mechanisms

•

Use analytical expertise to quantify data

•

Understand available plant and equipment

•

Collaborate with other disciplines

Some Difficult Decisions

• CHOICE of synthetic route

• WHEN to scale up

• WHETHER to scale up more than one route

• WHICH route to use to make initial supplies

• WHEN to change route

It is often better to “quickly” scale up one route whilst looking for a better one

BUT

There is a danger of getting “locked in”

First 10-20 Kg are the most difficult

• If the route is NOT likely to be used in manufacturing - Carry out minimal optimization

- Improve work-ups and isolations - Ensure safety for scale-up

- Go into plant ASAP

- Make kilogram supplies

• If the route IS likely to be used in manufacturing - Take a longer term approach

- Aim to understand the process

Cost and Safety Considerations

Costs:

• If raw materials are EXPENSIVE

- Concentrate effort on yield maximization

• IF raw materials are CHEAP

- Concentrate on improving process efficiency (work-up and isolation)

• Before starting development - Review synthetic route

Safety:

• What must be changed to make the process SAFE to scale up?

- Reagents (phosgene, diborane, acetylene, diazoalkanes, LDA?) - Exotherms

Process Considerations

• Is the order of steps most appropriate for the route?

- Linear vs convergent syntheses - Selectivity (example)

- Last step - does it involve heavy metals?

Can they contaminate the final product?

Synthesis of McN-5691: Palladium-catalyzed coupling reaction

OCH₃

N H₃C

CH₃

O I H₃C

OCH₃

Pd(0), CuI Solvent

+ H C C

OCH₃

N H₃C

CH₃

C O

H₃C

OCH₃

C

Attempts to Reduce Palladium in McN-5691

Work-up Procedure ppm Pd

1 Extraction, filtration, treatment with borohydride in methanol

2 Hydrogenation in ethanol in presence of carbon

3 Treatment of methylene chloride solution of product with

borohydride on alumina or silica 4 Chelation with dimethylglyoxime 5 Treatment of methylene chloride

solution of product with Amborane

100-200

930-950

770-870 259

H₃CO

N CH₃ H₃C

C O

H₃C

OCH₃

C Pd

+

Revised Synthesis of McN-5691

O

I

O

+ H C C Ph Pd(0), CuI O

C

O

C Ph

NaCNBH₃

OCH₃ OCH₃ H₂N

H₃CO

N H H₃C

C O

H₃C

OCH₃

C

H₃CO

N CH₃ H₃C

C O

H₃C

OCH₃

C NaBH₄

CH₂O Et₂NH

Can Steps be Easily Combined?

• Advantages

- Yields usually higher (product loss on work-up minimized)

- Eliminates isolation, purification, drying, analysis of one or more intermediates

- Usually produces cheaper product

• Disadvantages

- Impurities may carry through - Often lower product quality

- Optimum solvent for 1st step may not be same as for 2nd step - Process investigation of problems on plant or “failed“ batches

more difficult

Cyclization

Dehydrogenation

One-Step Dehydrogenation

C.G.M. van de Moesdijk, + 3 H₂

N

H CH₃+ 50 kcal/mol

α-Picoline gas phase

N CH₃

H₂C H₂

C CH₂ + H₂O

- 10 kcal/mol

A New Synthesis of α-Picoline

H₂C C

H₂ C CH₂

O C CH₃ N

+ 3 H₂

NH CH₃

+ H₂O - 60 kcal/mol

α-Pipecoline Ni, 120 °C

5 M Pa

liquid phase

Combination of Steps

•

Always worth trying

•

Optimize reaction steps independently

•

Understand both processes fully - then combine

•

Try to eliminate work-up in first reaction

• Old process

• New process:

Use formic acid as reducing and formilating agent

HCO₂H

HN N O

NH₂ O

C₃H₇

HN N O

NH₂ O

C₃H₇ NH₂ 1) NaNO2/HCl

2) Na2S₂O₄

H.J. Federsel; Astra

HN O

NHCHO

HN

O H HN N

O

NaNO_2, HCO₂H/Pt-C

General considerations

• These questions

- may DELAY scale-up

- are unlikely to result in the process being abandoned

• Almost ANY process can be scaled up if - engineered

- safety issues are addressed - process control is excellent - process limits are understood

eg boron tribromide, thallium reagents, alkyl lithiums

Process Optimization

The most important decision is

WHICH STAGE TO EXAMINE

• Costing will help

• Need to replace reagent or raw material?

• Step unlikely to be suitable for plant?

• Elimination of chromatography

Optimization - Yield Improvement

• Correct choice of reaction conditions

• Attention to detail

• Understanding the chemistry

- Mechanism - Byproducts

- Competing processes

• Good analytical methods

- Weight-based assays

- Standards

The Investigative Approach

• Obtain weight balance (prep HPLC?)

- Accurately determine isolated yield

• Assess yield after reaction but before work-up -

Is yield lost because reaction is poor?

- Is product lost during work-up?

• Follow reaction quantitatively - e.g. using hplc?

- Does yield peak at any stage?

• Was starting material pure?

- Check manufacturers’ figures

- Does recryst. of starting material improve yield?

Has the reaction gone to completion?

• Is there starting material left?

- increase time

- increase amount of reagent

- (may be reaction or complexing with product)

• Has starting material reacted

- with more than one mole of reagent?

- with solvent or adventitious water?

• Is the order of addition sensible for the process?

- Is it appropriate for the plant?

- (e.g. alkylation of primary amines with alkyl halides)

• Are the reagents of known purity?

Was product formed but reacted further?

• Examine effect of extended reaction time - Exaggerate the effect

- Isolate impurities

• If secondary reaction is a problem - Use deficiency of reagent

- Stop reaction at earlier stage

- Investigate effect of temperature

ArCHO + NaCN I

OPr OMe Ar =

DMF ArCHO ArCO₂H

14 % 6 %

OH Ar O

Ar 60 %

OCOAr Ar

O

Ar 14 %

CO₂Bu^t

OCOAr Ar

O

Ar 7 % ArCO₂H

Ar 9 %

O CO₂Bu^t 51 %

A.S. Thompson et al. J. Org. Chem. 1992, 7044-52

Synthesis of PAF Antagonist MK-287

Byproducts from Solvents

• Acetone in isopropanol

• Aldol reactions with aldehydes

• Dimethylamine in DMF

• Reacts with active molecules

• Methanol in ethanol

• Transesterification

• Dichloromethane

• Far more reactive than is appreciated

• e.g. with amines, sodium azide, ..

• Polyaromatic in benzene/toluene

Competing Processes

• Isolate and characterise ALL by-products

- Recrystallise product, then evaporate liquors

- Chromatography (prep. TLC, column, prep. HPLC) - Structure gives clues to mechanism

• Synthesise impurities in large amounts may be useful

- for analysts

- for taking through synthesis

• Examine effect of changing reaction conditions on impurity

level

Competing Processes

t-BuOH conc. H₂SO₄

urea

+ N N

Cl HO N N

Cl HO

t-Bu

t-Bu

N N Cl HO

t-Bu

N N Cl HO

t-Bu By-product formed on scale-up caused by extended reaction time on plant

Byproducts in Reactions -

Baylis-Hillman - Revised Process

CH

₂

O, H

₂

O CO

₂

Bu

^t

quinuclidinol 10 min. 80 °C

CO

₂

Bu

^t

CH

₂

OH

Byproducts

Bu^tO₂C

O CO₂Bu^t

Bu^tO₂C

O CO₂Bu^t nO

Bu^tO₂C

O nOBu^t

(CH2O)_n CO₂Bu^t

dipolar solvent

CO₂Bu^t CH₂OH quinuclidine

Bu^tO₂C

O CO₂Bu^t nO

in the presence of water

byproducst

Final Process:

 Add CH₂O, CH₂=CHCO₂Bu^t, to quinuclidine, water and cosolvent.

 heat, then add toluene, cool, separate

Baylis-Hillman - Revised Process

Understand Reaction Mechanism

Process for Manufacturing of Morpholine

42% Ni on Al OH

180-220°C DEGA

HO O

+ NH₃ / H₂O

Ni

NH₂ HO O

NH O

+ H₂O

C.A. Cooper, Chemtech, 1991, 378.

D.D. Dixon, U.S. Patent 4,645,834, 1987

Possible Byproducts

HO O

N H HO O

N

O

O OH

H

₂

N O N

O

N O N

O O

Other byproducts arise from oxidation

of alcohols

RCH

₂

OH RCHO + H Ni

₂

(slow step: control kinetics)

RCHO + NH

₂

R RCH=NHR’ + H

₂

O

or RCH-NHR’

Reduction or

OH

hydrogenolysis

RCH=NHR’ RCH H

_{2 2}

NHR’ + H

₂

O

Note: Amines also undergo nickel catalysed dehydrogenation

Mechanism of Ni catalysed amination

Selective Preparation of o-Hydroxybenzaldehydes

CHO CH₂O

OH

Mg(OMe)2

OH CH₂O

CH₂OH OH

< 50 ppm p-hydroxy!!

Used for the manufacture of:

CH=NOH OH

Byproduct is: ^OH

R

OH

R

Work-Up

• Many low-yielding processes result from poor isolation technique

- examine the aqueous stream

• Study chemical properties of product

- Especially solubility

• Exploit differences between product and by-products

- Solubilities

- Hydrophilic/hydrophobic nature - pK_a

- Molecular weight

• Material balance

• DESIGN the work-up for each process

Work-Up & Optimisation

• During optimisation studies work-up is also a variable

• Work-up may vary with solution yield

• Better NOT to work-up

- Saves time

- Relies on good analytical procedures

• Design work-up later

Remember: Murphy’s Law 2

The more innocuous a process change appears, the further

its influence will extend

Streamlining the Process/Optimization

Further development to improve

• Cost

• Ease of scale-up

• Work-up

• Process simplification

• Yield

• Change of Process Variables

• Optimum conditions will rarely be reached by one-step-at-a-time (OVAT) variations

• Optimum for one parameter (e.g. stoichiometry) will probably change as another parameter (e.g. concentration) is varied

• Changes in solvent are CERTAIN to change other parameters

OVAT Variations

20 40 60 80 100

Conc. (g/g)

20 40 60 80 100 Temperature °C

40 60 Path 1 80

Path 2

50 70 90

Change of Reagent

• To improve yield

• To improve selectivity

• To reduce cost

• To control effluent

• Example

- Investigative development in the Cefoxitin process

L. Weinstock, Chem. & Ind., 1986, 86

N S

TsCl

MeOCH₂Cl CH₂OCONH₂

CO₂H O

N OMe O

NH₂ CO₂H

H

N S

CH₂OCONH₂ CO₂^-

O

N OMe O

NHTs CO₂^-

H

N S

CH₂OCONH₂ CO₂CH₂OMe

O

N OMe O

NH₂

CO₂CH₂OMe H

N S

CH₂OCONH₂ CO₂H

O

N OMe O

H

S

Cephamycin C

Cefoxitin

i) TMS Me-carbamate or 4A molecular sieve ii) H⁺

S CH₂COCl

Cefoxitin Process

R. Tyson, US Patent 2,168.699, 1988; Chem. & Ind., 1988, 119

O N O N

H₂N CH

H

S CH₃ CH₃

O

O OCO₂Et H₃C

Ph

• Effective orally -well-adsorbed

• Ethoxycarbonyl group metabolised to ethanol and carbon dioxide

• 1 -Chlorodiethyl carbonate available in bulk BUT

Astra Bacampicillin Process

Astra Bacampicillin Process

SOLUTION: Use more reactive reagent - bromodiethyl carbonate PROBLEM: Not commercially available

SOLUTION: Contract out synthesis

Initially

Subsequently

 Process scaled up by Palmer Research 35 t/a

H₃C H C O Cl

CO₂Et H₃C H C O Br

CO₂Et

H₃C H C O Br

CO₂Et hν

Br₂ (EtO2)2CO

Rate & Order of Addition of Reagent or Catalyst

• Order of addition MAY be changed to facilitate scale-up

• Rate of addition WILL change on scale-up -the effect should be studied

- Exotherms - Yield variation

- By-product formation

• Therefore RECORD rate of addition in ALL lab and pilot

experiments

Importance of Controlling Addition Rate

Org Syn Process -

add all reagents and heat to 80°C 30 - 35% yield on scale-up

*Better for scale-up -

malonic acid O

CO₂H piperidine

pyridine

CO₂H CO₂H CO₂H

CO₂H

OH

Stoichiometry

• Often requires very careful control - e.g. Cefoxitin

• Changes during reagent addition

• Not always as expected from mechanistic reasoning - Friedel-Crafts with aluminium trichloride

- Alkylations with sodium hydride

• Require accurate assay methods for reagents and starting materials

Stoichiometry Differences:

• Overall

• IN solution at any one time

• Affected by rate of addition AND rate of reaction (and vice versa)

Synthesis of Benzazepines

solvent CH₂Cl

X

Mg CH₂MgCl

X

H₂ C

X

CH₂

O NR

X

X

NR HO

X

NR

Use of Organometallic Reagents

To get good yields in Grignard reaction

•

Grignard must react as soon as formed

•

Cannot make 1 mole of Grignard first - it couples to bibenzyl

•

Separately but simultaneously add benzyl chloride and oxazolidine to magnesium - good yields

•

Yield depends on ability to control rates

•

If oxazolidine added to quickly - reaction killed

•

Cannot mix benzyl chloride and oxazolidine - slow quaterniz.

Scale-Up of Butyl Lithium Chemistry

•

On scale-up, prefer to charge butyl lithium first

•

Affects anion vs. dianion formation

•

Work-up gives evolution of butane

A

50% hydrogen peroxide

sodium tungstate cat.

B

•

^Process

- Aqueous solution of sodium tungstate pre-treated with 50%

hydrogen peroxide (3 moles/mole A)

- Added to aqueous solution of A over 90 minutes

•

^Yields

- In development lab > 90%

- In safety lab (automated dosing) 9%

•

Experimental conclusion

- Add 10% of solution all at once, followed by dosing of rest of solution - Yield 97-100%

Effect of Rate of Addition

Dropping Funnel Test

0 30 60 90

0 0.2 0.4 0.6 0.8 1.0

Time (min)

W. Fr. Charge Delivered

Linear 90 min. Rate

3.0 3.5

Variation of Temperature

• Changes reaction rate (ca. × 2 every 10°C)

• Alters selectivity

• Exothermic reactions may be best carried out at HIGHER temperature to prevent accumulation

• Must control temperature accurately, especially during exothermic processes

• Study effect of overheating on process

- Decomposition?

- Runaway?

- Low yield?

- Loss of selectivity?

Decarboxylation Reaction

aq. base NH

N

CO₂Et O

NH N

CO₂H O

NH N

Dowterm A O

or PhOPh 250°C

0 10 20 30 40 50 60

0 50 100 150 200 250 300

Yield (%)

OH OH HO

OH OH HO

COOH

OH HO

(aq)

, t KHCO₃

∆

Temperature Control Can Be Critical

•

Equilibrium mixture of cis & trans isomers produced

•

In lab, with slow addition of hexane, only trans isomer isolated

•

cis Isomer is oil, so if isolated with trans a slow-filtering sticky product obtained

•

Process requires hexane addition at 50°C over several hours

•

Process worked well on 2000 L scale

•

At 10,000 L scale, sticky crystals obtained at 50°C

•

Good quality product if hexane added at 55°C

Dr S. Bone, “Scale-Up of Chemical Processes”, Brighton, Sept 1994 (conference organised by Scientific Update)

Temperature Control Can Be Critical

NaH, HCO₂Et R

O

OEt O

solvent, 0°C R O

OEt O

OH 50°C NO PRODUCT

(CO + NaOEt)

Minor Change of Intermediate

• Change in protecting group

• Change in ester

- To increase/decrease rate of reaction - To improve selectivity

• Change in salt form of intermediate

- To improve isolation

• Change in leaving group

- To change rate of reaction - To change selectivity

- To reduce cost

Variation of Pressure

• Usually only varied in gaseous reactions

- Catalytic hydrogenation - Ammonia reactions

- Carbonylation

• Very high pressures (10-20 kbar) will affect solution-phase reactions

- with high negative activation volumes - e.g. cycloaddition reactions

Time

• Time costs money

• Reduce plant occupation by simplifying reactions

• Increase rate by increasing temperature, concentration, pressure

• Kinetic studies assist chemical engineer

Concentration/Volume Efficiency

• Traditional research methods use dilute solutions

• Plant methods require the process to be as concentrated as possible

• Need to study effect of concentration on

- Yield

- Exotherm hazards - Rate of reaction

- By-product formation

• Need to minimise work-up volumes

Optimisation - Quality of Materials

• Use raw materials of comparable quality to those to be used on plant

• Ideally optimise using intermediate/raw material from I large batch of TYPICAL quality

• Periodically check quality of intermediates, raw materials and catalysts

- Do they deteriorate on storage?

- Do they pick up moisture?

Optimisation - Quality of Materials

• Check quality of solvents, particularly water content

• Carry out use-tests on

- raw materials from new suppliers - batches of in-house intermediates - new batches of critical materials

- (the supplier may be developing his process too, and quality may vary within the specification)

• Ask suppliers what impurities are in their raw materials

- Get a material balance

References

1. Optimization of Chemical Processes, 2^nd Ed., T.F. Edgar, D.M.

Himmelblau and L.S. Lasdon, McGraw-Hill, Boston, 2001

2. Ming Ge, Qing-Guo Wang, Min-Sen Chiu, Tong-Heng Lee, Chang- Chieh Hang, Kim-Hock Teo, An Effective Technique for Batch

Process Optimization with Application to Crystallization, Chemical Engineering Research and Design, Volume 78, 2000, 99-106.

3. Babu, B.V., Process Plant Simulation, Oxford University Press (2004).

4. Kalyanmoy, D., Optimization for Engineering Design, Prentice Hall (1998).