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

Solvent Selection Factors

July/2012 5

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

1

2

6

3

4

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

July/2012 12

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%

15%

20%

25%

30%

35%

40%

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

1

2

3

4

5

6

6

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