Development and Optimizationthe investigative approach

Attilio Citterio / Dept. CMIChttp://iscamap.chem.polimi.it/citterio/dottorato//

PhD IN INDUSTRIAL CHEMISTRY AND CHEMICAL ENGINEERING (CII)

Attilio Citterio

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• Aim to OPTIMIZE the process

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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

BUTThere is a danger of getting “locked in”

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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

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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- Concentrations

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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

NH3CCH3

IOH3C

OCH3

Pd(0), CuISolvent

+ H C C

OCH3

NH3CCH3

COH3C

OCH3

C

C.A. Maryanhoff, Cat. Org. React., 1988, 359

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Attempts to Reduce Palladium inMcN-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 dimethylglyoxime5 Treatment of methylene chloride

solution of product with Amborane resin

100-200

930-950

770-870259

112

H3CO

NCH3

H3C

COH3C

OCH3

C

Pd

+

Possible Palladium Complex

Attilio Citterio

Revised Synthesis of McN-5691

O

I

O

+ H C C Ph Pd(0), CuIO

C

O

C PhNaCNBH3

OCH3

OCH3H2N

H3CO

NH

H3C

COH3C

OCH3

C

H3CO

NCH3

H3C

COH3C

OCH3

C

NaBH4

CH2O

Et2NH

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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

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Cyclization

Dehydrogenation

One-Step Dehydrogenation

C.G.M. van de Moesdijk,Chem. & Ind., 1966, 129

+ 3 H2NH

CH3+ 50 kcal/mol

α-Picoline

gas phase

N CH3

H2CC

H2C

CH2C

O CH3NN CH3

+ H2O- 10 kcal/mol

α-Picoline

A New Synthesis of α-Picoline

H2CC

H2C

CH2C

O CH3N

+ 3 H2

NH

CH3

+ H2O - 60 kcal/mol

α-Pipecoline

Ni, 120 °C

5 M Paliquid phase

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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

NH2OC3H7

HN

N

O

NH2OC3H7

NH21) NaNO2/HCl

2) Na2S2O4

H.J. Federsel; Astra

N-propyl-6-aminouracil N-propyl-xantine

HN

N

O

NH2OC3H7

NHCHO HN

N

O

OC3H7

N

HNHN

N

O

NH2OC3H7

NaNO2, HCO2H/Pt-C

95 % yield

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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

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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

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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

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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?

Attilio Citterio

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?

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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

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ArCHO + NaCN

I

OPr

OMe

Ar =

DMF ArCHO ArCO2H14 % 6 %

OH

ArO

Ar 60 %

OCOAr

ArO

Ar 14 %

CO2But

OCOAr

ArO

Ar 7 %

ArCO2H9 %Ar

O CO2But

51 %

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

Synthesis of PAF Antagonist MK-287

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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

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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

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Competing Processes

t-BuOHconc. H2SO4urea

+

NN

HOCl NN

HOClt-Bu

t-Bu

NN

HOCl

t-Bu

NN

HOClSO3H

t-Bu

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

D.M.B. Hickey et al. J. Chem. Soc. Perkin 1, N. Lewis, Chem. & Ind., 1988, 109

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Byproducts in Reactions -Baylis-Hillman - Revised Process

CH2O, H2OCO2But

quinuclidinol 10 min. 80 °C

CO2But

CH2OH

P. Dunn, Pftizer

Byproducts

ButO2CO

CO2But

ButO2CO

CO2ButOn

ButO2CO OButn

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(CH2O)nCO2But

dipolar solvent

CO2But

CH2OHquinuclidine

ButO2CO

CO2ButOn

in the presenceof waterbyproducst

Final Process:

Add CH2O, CH2=CHCO2But, to quinuclidine, water and cosolvent. heat, then add toluene, cool, separate toluene layer - next stage optimize on cost: 70 % yield aqueous layer + catalyst used for next batch optimize on yield 90 %

Baylis-Hillman - Revised Process

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Understand Reaction MechanismProcess for Manufacturing of Morpholine

42% Ni on AlOH180-220°C DEGA

OHO+ NH3

/ H2O

Ni

NH2OHO

NH

O+ H2O

C.A. Cooper, Chemtech, 1991, 378.D.D. Dixon, U.S. Patent 4,645,834, 1987

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Possible Byproducts

OHO

NH

OHO

NO

OOH

OH2N NO

ON NOO

Other byproductsarise from oxidation

of alcohols

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RCH2OH RCHO + H2Ni

(slow step: control kinetics)

RCHO + NH2R RCH=NHR’ + H2O

or RCH-NHR’OHReduction or

hydrogenolysis

RCH=NHR’ RCH2NHR’ + H2OH2

Note: Amines also undergo nickel catalysed dehydrogenationand undergo the same reactions as above

Mechanism of Ni catalysed amination

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Selective Preparation of o-Hydroxybenzaldehydes

CHO

CH2O

OH

Mg(OMe)2

OH

CH2OCH2OHOH

< 50 ppm p-hydroxy!!

Used for the manufacture of:

CH=NOHOH

C9H19

Byproduct is:OH

R

OH

RDepends on amounts of free methanol present

Need to make Mg(OMe)2 methanol free- use toluene solvent, distill out free methanol.

D. Levin Zeneca, SCI Process Dev. Symp. 1993

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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- pKa- Molecular weight

• Material balance• DESIGN the work-up for each process

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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 2The more innocuous a process change appears, the further its influence will extend

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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

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OVAT Variations

20

40

60

80

100

Conc. (g/g)

20 40 60 80 100 Temperature °C

40

60

80Path 1

Path 250

70

90

The Development Chemist’s experience is that MOST reactions can be optimised to over 90% yield

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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

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N

STsCl

MeOCH2Cl

CH2OCONH2CO2H

O

NOMe

O

NH2

CO2H

H

N

S

CH2OCONH2CO2

-O

NOMe

O

NHTs

CO2-

H

N

S

CH2OCONH2CO2CH2OMe

O

NOMe

O

NH2

CO2CH2OMe

H

N

S

CH2OCONH2CO2H

O

NOMe

OH

S

Cephamycin C

Cefoxitin

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

SCH2COCl

Cefoxitin Process

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

NO

NO

CHH2N

HS CH3

CH3

OO OCO2Et

H3C

Ph

• Effective orally -well-adsorbed• Ethoxycarbonyl group metabolised to ethanol and carbon dioxide• 1 -Chlorodiethyl carbonate available in bulk

BUT• Forcing conditions required to esterify, causing degradation

Astra Bacampicillin Process

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Astra Bacampicillin Process

SOLUTION: Use more reactive reagent - bromodiethyl carbonatePROBLEM: Not commercially availableSOLUTION: Contract out synthesis

Initially

Subsequently

Process scaled up by Palmer Research 35 t/a

Subsequently Astra built plant at Sarajevo 150 tla

H3C HC O

ClCO2Et

H3C HC O

BrCO2Et

H3C HC O

BrCO2Et

hν

Br2(EtO2)2CO

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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

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Importance of Controlling Addition Rate

Org Syn Process - add all reagents and heat to 80°C30 - 35% yield on scale-up

*Better for scale-up - add crotonaldehyde to otherreagents

malonic acidOCO2Hpiperidine

pyridine

CO2H

CO2H

CO2H

CO2H

OH

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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)

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Synthesis of Benzazepines

solvent

CH2Cl

X

Mg CH2MgCl

X

H2C

X

CH2

NRO

X

XNR

HO

XNR

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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• Toluene – THF ; Hexane - THF

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A50% hydrogen peroxidesodium 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%

D. Knoechel (Upjohn), presented at “Scale-Up of Chemical Processes”, Brighton, 1994.

Effect of Rate of Addition

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Dropping Funnel Test

0 30 60 900

0.2

0.4

0.6

0.8

1.0

Time (min)

W. F

r. C

harg

e D

eliv

ered

Linear 90 min. Rate

3.0

3.5

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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?

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Decarboxylation Reaction

aq. base

NH

N

CO2Et

O

NH

N

CO2H

O

NH

N

ODowterm A or PhOPh

250°C

0

10

20

30

40

50

60

0 50 100 150 200 250 300

Yiel

d (%

)

Temperature (°C)

OH

OHHO

OH

OHHOCOOH

OH

OHHO

(aq)

, t

KHCO3

∆

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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)

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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)

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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

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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

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Time

• Time costs money

• Reduce plant occupation by simplifying reactions

• Increase rate by increasing temperature, concentration, pressure

• Kinetic studies assist chemical engineer

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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

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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?

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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

Attilio Citterio

References

1. Optimization of Chemical Processes, 2nd 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).