A New Ether Process Solvent: Cyclopentyl methyl ether (CPME)

for Green Chemistry and Process Innovation

OMe

Industrial Green Chemistry World, 7 December 2013, MumbaiShunji Sakamoto

Glycol-ethersDMSO

DMF

Boilin

g P

oin

t

MTBE

IPETHF

Polarity(Dielectric Constant)

100℃

180℃

HighLow

CPME

AcOEt

Toluene

Dioxane

Et2O

MeTHF

Positioning of CPME Among Other Solvents

CPME THF MeTHF Et2O Dioxane MTBE

Density (20°C) [g/cm3] 0.86 0.89 0.85 0.71 1.03 0.74

Vapor specific gravity (air = 1) 3.45 2.49 2.97 2.56 3.3 3.03

Boiling point [°C] 106 65 80 34.6 101 55

Melting point [°C] <-140 -108.5 -136 -116.3 11.8 -108.7

Viscosity (20°C) [cP] 0.55 0.55 0.6 (25˚C) 0.2448 1.31 0.35

Surface tension (20°C) [mN/m] 25.17 26.4 Unknown 17.3 33.74 19.8

Vaporization energy (bp) [Kcal/kg] 69.2 98.1 89.7 86.08 98.6 81.7

Specific heat (20°C) [Kcal/kg∙K] 0.4346 0.469 Unknown 0.5385 0.41 0.51

Refractive index (20°C) 1.4189 1.407 1.406 1.353 1.422 1.369

Solubility parameter [(cal/cm3)1/2] 8.4 9.5 8.52 7.4 Unknown Unknown

Dielectric constant (25°C) 4.76 7.58 7 4.197 2.227 2.6

Dipole moment [D] 1.27 (calcd.) 1.7 Unknown 1.12 0.45 1.4

Azeotropic temperature with water [°C] 83 (a) 64 71 (b) 34.2 87.8 52.9 (c)

Solubility of solvent in water (23°C) [g/100g] 1.1 Infinite 14 6.5 Infinite 4.8

Solubility of water in solvent (23°C) [g/100g] 0.3 Infinite 4.4 1.2 Infinite 1.5

Flash point [°C] -1 -14.5 -11 -45 12 -28

Auto Ignition Temperature [°C] 180 205 270 180~190 180 224

LogPow 1.59 0.47 Unknown 0.89 -0.42 0.94

Explosion range [vol%] Lower limit 1.1 1.84 1.5 1.85 2 1.6

Upper limit 9.9 11.8 8.9 48 22 8.4

Comparison with other Ethers

1. Green ChemistryHigh Recovery Rate > 90% --- High HydrophobicityReduces amount of wastes and CO2

Diverse uses as reaction, extraction and crystallization solvents --- Solvent unification, Reduction of solvent amount

Low peroxide formationManufactured by atom economical processMakes Azeotrope with water : 16% water at 83℃

2. Process InnovationDiverse uses as reaction, extraction and crystallization solvents

--- Reduction of solvent exchangeProcess simplification and shortening One-pot synthesis and telescoping Stable under acidic and basic conditions

Summary of CPME Benefits

The Contribution of CPME to Green Chemistry

Reduction of wastes and CO2 Emissions with CPME

ZEON’s Manufacturing Process of CPME

+ MeOH

Molecular Weight 68.12 + 32.04 = 100.16

100% Atom Economical Reaction

No atom waste

One-step continuous system --- energy saving

OMe

Acid Cat.

Peroxide Formation in CPME versus other ethers

The 12 Principles of Green Chemistry

1. PreventionSignificant reduction of water and solvent waste

2. Atom EconomyWe manufacture CPME by the atom economical reaction.

3. Less Hazardous Chemical Syntheses4. Designing Safer Chemicals5. Safer Solvents and Auxiliaries

CPME makes slight peroxides. We manufacture CPME with minimum auxiliaries.

6. Design for Energy EfficiencyCPME can save energy by simplification and shortening of production processes.

7. Use of Renewable Feedstocks8. Reduce Derivatives

We manufacture CPME in the one-step continuous system without derivatizations.

9. CatalysisWe manufacture CPME in the catalytic process in the presence of the solid acid.

10. Design for Degradation11. Real-time analysis for Pollution Prevention

The flow reaction process is continuously monitored.

12. Inherently Safer Chemistry for Accident PreventionCPME has lower formation of peroxides in comparison with common ethers.

CPME meets 8 principles

The Contribution of CPME to Process Innovation

Fixed cost reduction with CPME

CPME shortens and simplifies the process--- saves process time, facilities and labor

--- fixed cost reduction

Variable Cost Reduction with CPME(with solvent recovery)

(Waste solvent, Waste water)C Waste Disposal Cost ($0.5/kg)

CPME THF

$8 x 10 x 0.1 = $8//kg - product $4 x 10 x 0.4 = $16/kg - product

CPME: $0.5 x 10 x 0.1 = $0.5

water: $0.5 x 3 = $1.5

THF: $0.5 x 10 x 0.4 = $2.0

AcOEt: $0.5 x 10 x 0.1 = $0.5

water: $0.5 x (40+20+20) = $40

AcOEt ($1.2/kg)

$1.2 x 10 x 0.1 = $1.2

$59.7/kg-product

2 weight times of water, aqNaCl to Solvent

4 weight times of water

to Solvent

recovery rate = 90% recovery rate = 60%

Total Variable Cost (A+B+C)

A Reaction Solvent Cost

Solvent/Product = 10/1(by weight)

B Extraction Solvent Cost

MeTHF

recovery rate = 70%

$6 x 10 x 0.3 = $18/kg - product

MeTHF: $0.5 x 10 x 0.3 = $1.5

AcOEt: $0.5 x 10 x 0.1 = $0.5

water: $0.5 x 6 = $3

$24.2/kg-product

AcOEt ($1.2/kg)

$1.2 x 10 x 0.1 = $1.2

equal weight of water to

product

equal weight of water, aqNaCl to product

4 weight times of water to

product

Extraction solvent:

unnecessary!

($8/kg) ($6/kg) ($4/kg)

CPME MeTHF THF

* The prices used here are only to demonstrate their cost reduction with CPME. The actual prices would

vary according to conditions such as quality, quantity, location, time, etc.

$10.0/kg-product

Stability of CPME to Acid and Base

Example of Green Chemistry & Process Innovation PINNER REACTION (1)

Requirements for Solvent

stability to acid solubility of raw materialsinsolubility of product

R OCH3

NH4M-HCl solution, CH3OH

solvent, 0oC, 1 h, then 0-5 oC, 48 h

solution solvent Yield (%)

CPME CPME 89b)

a) U.S.Pat.No.: US 6806380 B2b) Work-up of CPME process is only filtration and washing.

R CN

R

CH3

H3CO

1,4-Dioxane Et2O 86a)

CPME CPME 90b)

CPME CPME 91b)

HCl

Solvent Unification

1. Reaction: CPME

2. Cooling

3. Filtration

4. Drying

Product

TelescopingSteps: 9 to 4Solvents: 2 to 1

Greener ProcessWithout:Dangerous Solvents

Example of Green Chemistry & Process Innovation PINNER REACTION (2)

CPME Process4 steps without dangerous solvents

Original Process9 steps with dangerous solvents

　　　Waste

1. Reaction: Et2O - Dioxane

2. Cooling:

3. Warmed at 40℃

4. N2 Bubbling

5. Removal of

solvent in vacuo

6. Precipitated by cooling

7. Addition of Et2O

8. Filtration

9. Drying

Product

Et2O

Dioxane

HCl

Et2O

Comparison of Properties of CPME & MeTHF versus THF

excellent good poor

CPME MeTHF THF

Solubility in water g/100g-water 1.1 14 Infinite

Recovery rate from water % 90 70 60

Waste rate (1 - recovery rate) % 10 30 40

Explosive Peroxide formation slower faster faster

Stability to acid more stable less stable unstable

Boiling Point °C 106 80 65

Flash Point °C -1 -11 -14.5

Vaporization Energy (at bp) kcal/kg 69.2 89.7 98.1

Acid and Base solutions in CPME

2. Process Innovation Process simplification - Fixed cost reduction Solvent unification - Variable cost reduction Facilitate one-pot synthesis and Telescoping Better stability under acidic and basic conditions

Conclusion

1. Green Chemistry – Cradle to Greave Manufactured by Atom economical process Solvent unification and reduction of solvent used Reduction of wastes and CO2

Saving energy Lower Peroxide formation

CPME contributes to:

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Specifications

Toxicity Data

ICH Guideline for Residual Solvents (Zeon)

CPME has not yet classified in ICH guideline for residual solvents (Q3C). However, it is assumed to be in Class 2 according to Zeon's own calculation.

1) Formula

PDE = (NOEL x Weight Adjustment)/(F1+F2+F3+F4+F5)

Concentration Limit (PPM) = 1000 x PDE / dose

*PDE: Permitted Daily Exposure

2) Calculation

PDE = (15x50) / (5 x 10 x 10 x 1 x 1)=1.5mg/day

Concentration Limit = 1000 x 1.5/10 = 150ppm

3) Conclusion

According to the above, Zeon assume CPME would be classified in Class 2.

ICH Guideline for Residual Solvents (Merck)

Antonucci, V et al.: Org. Process Res. Dev., Article ASAP, 10.1021/op100303c, March 18, 2011

PDE (mg/day)

CPME 7.4

MeTHF 6.2

THF 7.2*

Toluene 8.9*

*ICH Guideline

Grignard Reaction

Variable Cost Reduction with CPME(without solvent recovery)

(Waste solvent, Waste water)C Waste Disposal Cost ($0.5/kg)

CPME THF

$8 x 10 = $80//kg - product $4 x 10 = $40/kg - product

CPME: $0.5 x 10 = $5

water: $0.5 x 3 = $1.5

THF: $0.5 x 10 = $5

AcOEt: $0.5 x 40 = $20

water: $0.5 x (40+20+20) = $40

AcOEt ($1.2/kg)

$1.2 x 40 = $48

$153.0/kg-product

2 weight times of water, aqNaCl to Solvent

4 weight times of water

to Solvent

Total Variable Cost (A+B+C)

A Reaction Solvent Cost

Solvent/Product = 10/1(by weight)

B Extraction Solvent Cost

MeTHF

$6 x 10 = $60/kg - product

MeTHF: $0.5 x 10 = $5

AcOEt: $0.5 x 40 = $20

water: $0.5 x 6 = $3

$136.0/kg-product

AcOEt ($1.2/kg)

$1.2 x 40 = $48

equal weight of water to

product

equal weight of water, aqNaCl to product

4 weight times of water to

product

Extraction solvent:

unnecessary!

($8/kg) ($6/kg) ($4/kg)

CPME MeTHF THF

* The prices used here are only to demonstrate their cost reduction with CPME. The actual prices would

vary according to conditions such as quality, quantity, location, time, etc.

$86.5/kg-product

Comparison of Formation of Peroxides in MeTHF versus THF

Aycock, D. Org. Process Res. Dev., 2007, 11 (1), pp 156–159

Cumulative Energy Demand (CED)

Dr. Alireza BanimostafaETH Zurich Institute for Chemical and Bioengineering

CED Production: 95-100 (Mj/kg)

CED Incineration: 70-75 (Mj/kg)

CED Distillation: 25 (Mj/kg)

His paper will be published in AIChE journal in a few months as:"Retrofit design of a pharmaceutical batch process considering “green chemistry and engineering” principles"

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