The Scale-up of Chemical Processes Milan Italy July 9-11,...
Transcript of The Scale-up of Chemical Processes Milan Italy July 9-11,...
The Scale-up of Chemical Processes Milan Italy
July 9-11, 2012
Ron Leng The Dow Chemical Company
July/2012 1
Premise: Outline: Role of the Solvent
Solvent Selection Considerations
Approach to Making the Selection
Examples of Solvent Selection for Process Simplification
Example 1– 2,6-difluorobenzonitrile
Example 2 – Cyhalofop (Rice Herbicide)
Example 3 – Experimental Pesticide
July/2012 2
The selection of the solvent may be the most significant decision affecting the cost, simplicity, and operability of a chemical process
A Bit on Solvents Solvents have been around since ancient times*
Fermentation of vegetable matter to produce ethanol
Egyptians used solvents for cosmetics
Assyrians used solvents for eye compresses (mid 800 AD) *taken in part from Directory of Solvents, 1996, Blackie Academic
July/2012 3
~ $10 Bn sales in Eur/NA (2007)
2015 sales projected ~ 20 MM Mt
500, 000 European companies use solvents – Pharma & Agro
Msc internet sources
The annual average consumption of Aqua Vitae is 6 liter / person - WHO Fill the Colosseum in 7 days
The role of the solvent
Reaction step -- the organic chemist’s forte
Creates an environment where raw materials can come together to react and form useful products
Influences the rate, yield and selectivity
Product Isolation – Extraction, Crystallization, Distillation Permits recovery of the product in good yield
Rejects impurities to achieve desired product quality
Solvents must be recovered
Wastes must be treated
July/2012 4
Reaction
Separations
Waste Tmt
Utilities
BOP
Plant Capital
The reactor may be minor portion of capital
Holistic Solvent Selection Methodology
Questions to ask Functional Approach
Can the solvent be eliminated? Use phase transfer catalyst
Operate at more extreme conditions
Can excess reagent serve as the “solvent”?
Can the product or intermediate be used in place of the “solvent”?
Can “greener” solvents w/ similar properties be substituted?
Can a single solvent work for both reaction and separation steps?
Define the objectives for the solvent for the entire process
Translate these objectives into solvent properties
Chemical & Physical
Assemble a list of solvents w/ desirable properties
Use a rating tool to rank & screen solvents
Test/validate top choices in lab
Repeat the cycle to optimize
July/2012 6
How the Solvent Choice Simplified the Process
Taken from three Dow AgroSciences processes
July/2012 7
Ex 1 -- 2,6-Difluorobenzonitrile CN
+ 2 KCl
2,6-dichlorobenzonitrile
+ 2 KF
2,6-difluorobenzonitrile
Cl Cl
DCBN
CN
F F
DFBN
Sulfolane
230 C6 hrs
CN
X X
Di-halo BN
2)+ H2O
CN
X
CN
O X
biaryl-ethers
Key water related side reaction
X = Cl, F
July/2012 8
Intermediate to family of herbicides, 100’s of MT Halex Reaction uses polar, aprotic solvents, & spray dried KF <50 µ Near quantitative yield when anhydrous 1 mole H2O reacts w/ 2 moles of product to make biaryl ethers Fine, by-product KCl can be challenging to filter
Halide Exchange in Sulfolane
1. Typical solvent is high boiling, polar aprotic solvent
• Reaction must be dry
2. Fine co-product KCl is filtered1
3. Wash Solvent used to displace reaction solvent from cake
4. Washed salt is dissolved into water, distilled to recover wash solvent
5. Salt disposed of as aq. stream 6. Product separated from reaction
solvent by distillation 7. Solvent recovered by distillation
from heavies 8. Heavies are incinerated
Halide
Exchange
Salt
Filtration
Salt Cake
Washing
Brine
Stripping
Solvent
Recovery
Product
Distillation
2,6-DCBN
2.1 eq KF
Fresh Solvent
Wash
Solvent
Incinerator 2,6-DFBN
Aq. Disposal
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2
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3
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7 5
8
Recycle
Sulfolane
Lights Cut
July/2012 9
1 IPA (Independent Project Analysis, Inc) – ranks solids handling as a significant risk for new process technology projects
Solvent-Free Halex Process
1. No Solvent in reaction
• Use phase transfer catalyst
2. KCl is dissolved into water & decanted from organic phase
3. Organics stripped from brine
4. Product is distilled from under-fluorinated intermediates & catalyst -- recycled to reaction step
5. Tar purge every “n” batches
• Catalyst recovery by precipitation w/ Methanol (optional)
6. Heavies are incinerated
Halide
Exchange
Salt
Extraction
Brine
Stripping
Occasional
Tar Purge
Product
Distillation
2,6-DCBN
2.1 eq KF
Fresh Catalyst
Incinerator 2,6-DFBN Aq. Disposal
1
2
6
3
4
7
5
water
CFEP &
Catalyst
Recycle
Diluent
July/2012 10
Dibenzo-18-C-6 PTC
July/2012 11
CN
+ 2 KCl
2,6-dichlorobenzonitrile
+ 2 KF
2,6-difluorobenzonitrile
Cl Cl
DCBN
CN
F F
DFBN
5 mole % DB-18
230 C10 hrs
K+
F- Scaled to 7500 liter reactor 5 mole % Dibenzo-18-Crown 6 catalyst > 98% reaction yield Clean salt removal by aq. extraction
< 5 ppm DB-18 in KCl brine
Catalyst recycled in stream of partially converted CFBN 30-40 catalyst cycles before purge
Recovery of DB-18 from tars by methanol precipitation US Patent 5,502,235 - Solventless process for making 2,6 difluorobenzonitrile
Ex 2 -- Rice Herbicide
Cyhalofop (CHP): post emergent, grass herbicide
Volume ~ 100’s of Metric Tons per year
Launched in mid 90’s, sales primarily in Asia
Produced at a toll manufacturer
Business desired N.A. manufacturing site Market Shift
Drive to reduce tolling fee, freight, and duty costs.
The Challenge Develop a new supply option
Develop a new, simpler, cheaper process
Fit into existing assets
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CHF Chemistry OHO CH C
O
OH
CH3
MAQAcid
*O
+K
-O CH C
O
O-K
+
CH3
MAQAcid dipotassium salt
*
K2CO3
FNC
34DFBN
F
OO CH C
O
O-K
+
CH3
Cyhalofop acid potassium salt
*NC
F
CH3CH2CH2CH2Br
BuBr
OO CH C
O
OCH2CH2CH2CH3
CH3
Cyhalofop
*NC
F
NMP
The Approach Keep current chemical route
Replace NMP w/ Acetonitrile
July/2012 13
ACN
Develop new process w/ simpler sequence of Unit Ops
Old NMP Process
NMP is good reaction solvent
July/2012 14
Coupling &
Butylation
Reactions
Salt Filtration
& Toluene wash
Salt Cake
Dissolution
Brine
Treatment
Toluene
Distillation
4x Water
wash
H2O & NMP
Distillation
Polish
Filtration
Cyhalofop
Drumming
Water
MAQ acid
K2CO3
3,4-DFBN
Butyl Bromide
NMP Recycle
Incinerator
NMP
Toluene
Recycle
Disposal
Coupling &
Butylation
Reactions
Salt Filtration
& Toluene wash
Salt Cake
Dissolution
Brine
Treatment
Toluene
Distillation
4x Water
wash
H2O & NMP
Distillation
Polish
Filtration
Cyhalofop
Drumming
Water
MAQ acid
K2CO3
3,4-DFBN
Butyl Bromide
NMP Recycle
Incinerator
NMP
Toluene
Recycle
Disposal
Filtration of large amount of fine KF & KBr salt
Salt is wet w/ NMP – issue for brine treatment
Multi-stage extraction to remove
NMP from CHF
Use of 3:1 toluene for phase separation
Distillation of toluene from CHF
Distillation of 5:1 H2O from NMP
√
New Acetonitrile Process
– Reaction @ 135 °C & ~ 3 Bar Coupling &
Butylation
Reactions
ACN
Distillation
Brine
Treatment
Salt Extraction
& 2nd Aq. Wash
Azeotopic
Drying
Polish
FiltrationCyhalofop
Drumming
to WWTP
MAQ acid
K2CO3
3,4-DFBN
Butyl Bromide
Purge to
Incinerator
H2O
Molten
Cyhalofop
flux
Acetonitrile
Coupling &
Butylation
Reactions
ACN
Distillation
Brine
Treatment
Salt Extraction
& 2nd Aq. Wash
Azeotopic
Drying
Polish
FiltrationCyhalofop
Drumming
to WWTP
MAQ acid
K2CO3
3,4-DFBN
Butyl Bromide
Purge to
Incinerator
H2O
Molten
Cyhalofop
flux
Acetonitrile
July/2012 15
US Patent 8,071,804
+ Solvent distilled prior to salt removal
√
+ Use of CHP as flux for distillation
+ Liquid @ extraction temp
+ Water immiscible
+ Salts removed by aq. Extraction
+ No toluene to distill
+ No water to distill from solvent
+ Low organic brine, minimal
treatment needed
Key Process Challenges
MAQ dianion preparation Mixing a high viscosity slurry
Management of CO2 off-gassing
High solvent recovery Removal of excess reactants (BuBr, by-product H2O)
Heat history
Maintaining Product Purity/Specifications Minimization of racemization
Management of new or higher levels of any impurity for re-registration
July/2012 16
Scaling the Mixing Requirement
The Challenge Use of ACN causes very thick
dianion formation mixture Manage CO2 off-gassing
July/2012 17
Plant Pilot Plant Lab
Mix Time (sec) 30 6 1
Tip Speed (ft/sec) 30.4 13.6 5.4
Scale-up Approach Changed order of addition
Acid added to base minimizes K2CO3 decomposition
Scale Mixing on Power per Volume P/V ~ (RPM) 3 x (Dt)
5 / Vol 1-liter to 75 liter to 7500 liter
The Result Minimal CO2 off-gassing Slurry is thick but manageable Plant agitator will be modified
Idea for draining solids from a vessel Problem
Many slurries are difficult to completely remove from the vessel Requires extra rinse solvent
Heel may interfere w/ chemistry of next batch
Solution Install a Lightin KT-3 Tickler agitator
July/2012 18
http://www.lightninmixers.com/
US Patent 6,955,461
Solvent Recycle Removal of Butyl bromide & H2O
The Challenge ~ 10% excess BuBr used in alky’n,
leads to racemization in recycle
Some H2O from K2CO3 decomp.
The Data Volatility order (BP °C)
ACN (82) > H2O (100) > BuBr (104)
Form low bp ternary azeotrope
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
% o
f B
uB
r d
isti
lled
% of feed vaporized
BuBr Removal from Acetonitrile
285 mmHg 285 mmHg w/ CHF 760 mmHg w/CHF 18" Col 18" Col w/CHF
Feed: 94% ACN, 3% BuBr, 3% H2O
July/2012 19
Column
Flash
The Result Install 20 ft packed column
Recycle of > 85% ACN
Distillation & Thermal History
The Challenge: Minimize thermal decomposition
The Approach Modeled distillation column
(Pressures, flux, column diameter) to predict distillation profile
< 2hrs @ Tmax (~110 °C)
Verified distillation profile in lab
July/2012 20
y = 0.000091x + 0.004221
0.3%
0.4%
0.5%
0.6%
0.7%
0.8%
0 4 8 12 16 20 24 28 32
S/(
S+
R)
Time (hrs)
CHP Racemization @ 110°C
0
60
120
180
240
300
360
0
20
40
60
80
100
120
0 50 100 150 200
mm
Hg
Te
mp
C &
wt%
Minutes
Lab ACN Distillation @ 270 mmHG
Pot Temp % CHF in bottoms
Vapor mmHg
Pressure Reduced
@ end of Distillation
Isothermal aging studies @ Tmax
The Result Racemization rate of 0.01 – 0.03 %/hr
is acceptable
CHF Process Comparison Old NMP Process New ACN Process
Coupling &
Butylation
Reactions
Salt Filtration
& Toluene wash
Salt Cake
Dissolution
Brine
Treatment
Toluene
Distillation
4x Water
wash
H2O & NMP
Distillation
Polish
Filtration
Cyhalofop
Drumming
Water
MAQ acid
K2CO3
3,4-DFBN
Butyl Bromide
NMP Recycle
Incinerator
NMP
Toluene
Recycle
Disposal
Coupling &
Butylation
Reactions
Salt Filtration
& Toluene wash
Salt Cake
Dissolution
Brine
Treatment
Toluene
Distillation
4x Water
wash
H2O & NMP
Distillation
Polish
Filtration
Cyhalofop
Drumming
Water
MAQ acid
K2CO3
3,4-DFBN
Butyl Bromide
NMP Recycle
Incinerator
NMP
Toluene
Recycle
Disposal
Coupling &
Butylation
Reactions
ACN
Distillation
Brine
Treatment
Salt Extraction
& 2nd Aq. Wash
Azeotopic
Drying
Polish
FiltrationCyhalofop
Drumming
to WWTP
MAQ acid
K2CO3
3,4-DFBN
Butyl Bromide
Purge to
Incinerator
H2O
Molten
Cyhalofop
flux
Acetonitrile
Coupling &
Butylation
Reactions
ACN
Distillation
Brine
Treatment
Salt Extraction
& 2nd Aq. Wash
Azeotopic
Drying
Polish
FiltrationCyhalofop
Drumming
to WWTP
MAQ acid
K2CO3
3,4-DFBN
Butyl Bromide
Purge to
Incinerator
H2O
Molten
Cyhalofop
flux
Acetonitrile
July/2012 21
• Core Unit Operations reduced by 25% • Eliminated salt filtration • Eliminated extraction solvent • Permits high recycle of solvent
Implemented at 7500 liter scale
Experimental Pesticide
Coupling of sub. benzyl alcohol (BA) w/ chlorinated heterocycle (CH)
Requires a hindered tertiary alcohol
July/2012 22
Hindered alcohol solvent
Water is deleterious -- leads to “H1” Main side reaction is to bis-adduct
limit by excess BA Lower temperature
Goal is to develop scaleable process for 500kg pilot plant sample
H1 impurity Bis-Adduct
Background
Initial process: K-t-butoxide as base in t-butanol solvent 15% solution cost $17 / kg (@ projected commercial qty) Other solvents led to higher impurities
Switched base to KOH (much cheaper than K-butoxide) By-product water led to 10-15% yield loss to hydrolysis “H1”
H1 needed to be removed to level below 100 ppm
Azeotropic removal of water reduced hydrolysis Large amount of solvent, wet and difficult to recycle
Inefficient Product Isolation options Water & toluene extract / heptane anti-solvent crystallization Or salt filtration, anti-solvent precipitation w/ copious water
Idea: Replace t-butanol with t-amyl alcohol
July/2012 23
Hindered Alcohol Properties
Boiling Point (°C) 83 102
Melting Point (°C) 25 -12
Density @ 20 °C(g/cc) 0.775 0.805
Relative Reaction rate 1 0.5
Relative Unit Cost 1 2.5
Solubility in water miscible Partially miscible
Azeotrope (% H2O/°C) ~12% / 80 ~ 28% / 87
Dielectric Constant 12.5 5.8
Hildebrand Solubility Parameter
20.3 17.8
July/2012 24
t-butanol t-amyl alcohol
Alcohol / Water VLE
July/2012 25
t-amyl alcohol
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
75 80 85 90 95 100 105
Wt
% W
ate
r
Temp (C)
T-butanol / water VLE @ 1 atm
wt % H2O liq wt % H2O vap
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
75 80 85 90 95 100 105
Wt
% W
ate
r
Temp (C)
T-amyl alcohol/water VLE @ 1atm
liquid vapor
• t-butanol: homogeneous azeotrope – difficult to fractionate @ low water
[109] Krempin E.D., Dow Report, Rep.No. TMDP-3, 1977 [941] Quitzsch K., Kopp R., Renker W., Geiseler G., Z.Phys.Chem.(Leipzig), 237, p256-266, 1968
•t-amyl alcohol: heterogeneous azeotrope -- can be enriched by rectification
t-amyl alcohol / water LLE
Phase splitting of the distillate allows water to be purged
The mutual solubility are lower at elevated temp.
July/2012 26
0%
5%
10%
15%
20%
25%
30%
0 10 20 30 40 50 60 70 80 90 100 W
t %
Co
mp
A i
n P
ha
se B
Temp (C)
t-amyl alcohol & water LLE vs Temp
H2O in org T-aa in Aq
[20174] Stephenson R., Stuart J., Tabak M., J.Chem.Eng.Data, 29(3), p287-290, 1984
Addition of salt reduces water solubility in t-aa No salt 18-20% H2O
KCl: 10.5% H2O
NaCl: 7.3% H2O
Salt add’n decreases H2O solubility
Product Isolation
KCl is washed from reaction mixture w/ water first
Generated solubility data
H2O & BA increase solubility
Anti-solvent considered (aliphatic hydrocarbon) Crashed BA out, purity issue
Evaporation / Cooling
Recycle portion of filtrate to reaction step Increase in product yield
Permitted use of more BA to drive reaction rate
0%
5%
10%
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25%
30%
35%
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45%
50%
0 10 20 30 40 50 60 70
wt
% p
rod
uc
t
Temp C
Product solubility in t-amyl alcohol
100 % t-AA 88% t-AA mother liquor w/ 7% MBA
July/2012 27
Simplified 1 Pot Process
AlkoxideFormation & Drying
Coupling Reaction
KCl Extraction
Water Washof Org Phase
Evaporative Crystallization
& Cooling
FiltrationWashingDrying
t-AA & H2O to Solvent Recovery
t-Amyl alcohol
Water
chloro-heterocycle
Prod
benzyl alcohol
KOH (s)
Filtrates
t-amyl alcohol
Water
to solventrecovery
Aqueous phasetreatment
Portion of Filtrates Recycled to Reactor
Incineration
1. Azeo drying of rxn mix
2. KCl and H1 removed by aqueous extraction Multiple washes in same pot
3. Product crystallized by evaporation & cooling
4. Product recovered by filtration, washing, drying
5. Mother liquor recycled to reaction step:
6. Solvent recovered by distillation
July/2012 28
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Final Thoughts
Selection of the solvent one of the most significant choices you make in designing the process
The optimum solvent for the reaction may not be the best for the overall process
Capital requirements and operating costs for the product isolation, solvent recovery, and waste treatment processes are strongly dependent on the solvent used, and are usually much more significant than for the reaction equipment
A Holistic approach in which the impact on yield, purity, EH&S issues, regulatory issues, cost and supply should be used in making the solvent selection
THANK YOU!
July/2012 29
Useful Resources Directory of Solvents
B.P. Whim (Editor), P.G. Johnson (Editor)
Solvents and Solvent Effects in Organic Chemistry Christian Reichardt (Author), Thomas Welton (Author)
List of websites for Green Chemistry http://migreenchemistry.org/toolbox/directory/
ACS-GCI Pharmaceutical Roundtable Solvent Selection Guide (Version 2.0 Issued April 1, 2011) http://www.acs.org/gcipharmaroundtable
European Solvents Industry Group http://www.esig.org/
Practical Process Research & Development Neal Anderson
The Pilot Plant Real Book Francis McConville
July/2012 30