phd in industrial chemistry and chemical engineering …€¦ · attilio citterio aims of chemical...
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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
Attilio Citterio
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”
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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)
Attilio Citterio
Synthesis of Benzazepines
solvent
CH2Cl
X
Mg CH2MgCl
X
H2C
X
CH2
NRO
X
XNR
HO
XNR
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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?
Attilio Citterio
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
∆
Attilio Citterio
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)
Attilio Citterio
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)
Attilio Citterio
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
Attilio Citterio
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
Attilio Citterio
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?
Attilio Citterio
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).