Process intensification via OSN assisted synthesis ...nym14.ce.ic.ac.uk/sites/default/files/Dominic...

Confidential – © 2009, VITO NV – All rights reserved

New Young Membranes 14, London

Process intensification via OSN assisted synthesis: towards more environmentally benign chemical production D. Ormerod, A. Buekenhoudt, P. Vandezande

Vertrouwelijk – © 2009, VITO NV – Alle rechten voorbehouden

Outline

VITO short Process intensification of high dilution reactions

• Ouline of the problem • A solution via OSN • Experimental results

coupling catalyzed reactions to a membrane • Flow reactor results

conclusion


Flemish Institute of Technological Research

Oostende Berchem Mol


Facts & Figures • Founded in 1991 • Autonomous public research

company • Bridge between academia –

government and industry • 5-year framework contract • Nearly 600 people, 10 nationalities • Yearly budget of 70 MEUR


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leverage effect (expertise, assets, financial) for larger

scale research programs

Contract research

Technology transfer

Strategic projects

Open Innovation

BIODIESEL Company NV


Sustainable chemistry : Process Intensification

PI : bridge between 3 P’s


Vito-VID: background

Example : intramolecular macrocyclisation reactions Consequence • Low productivity of batch reactions • Higher production costs based on reactor and solvent use • Increased environmental impact of API production

Some reactions must be carried out at high dilution

+ reagents solvent

A real example from the pharmaceutical industry being formation of a 14-membered ring carried out at a dilution that in a 6000L reactor only ± 50 Kg product formed.


One solution

Features of the pseudo/simulated high dilution conditions : Slow addition of substrate at high dilution Reactor contains a relatively high concentration of reactants Better but still relatively high solvent use : 10 – 100 l/mol Better Process Mass Intensity (PMI) Not overall efficient : only kinetic product formation, no reversible reactions

Pseudo/simulated high dilution (Ziegler et al., 1955)

High concentration of reactants

Low concentration of substrate

Slow addition


Vito-VID: membrane controlled Volume Intense Dilution

FeedTank

reactionvessel

Membrane with relatively high rejection for solute but not 100%

Solution of reaction starting material at high concentration

Reaction reagents at high concentration

Due to membrane solution of starting material at low concentration

Membrane 2 with as high as possible rejection for all solutes in reactor

Due to solvent recovery by membrane 2 overall effect is reactions are carried out at high dilution but with low solvent use and peak volumes


Vito-VID: single membrane configuration

Alternative VID : conventional mixer for substrate addition

High concentration of substrate

Membrane 1 for solvent recovery

Mixer for slow substrate addition


Vito-VID: model reaction

Model reaction : macro-cyclization reaction Mitsunobu lactonization to form a 13-membered ring

OO

N

OH

O

OH

R

Chemical Formula: C32H41N3O6SMolecular Weight: 595.75

Chemical Formula: C32H39N3O5SMolecular Weight: 577.73

O N

OO

R

OPh3P, DIAD

Solvents : DCM, toluene or THF


Vito-VID: Batchwise reactions

Product yield in standard batch reactions

11.7

41.95

51.85 57.95

77.12

28.4

63.8

82.7

0

10

20

30

40

50

60

70

80

90

10 25 50 110 500

Yiel

d (%

)

L/mol solvent

Batchwise yield vs solvent volume -Mitsunobu lactonization

THF

dcm


Vito-VID: experimental results

Slow addition with an OSN membrane

Addition with : different membranes different concentration of substrate in feed solution

membrane Solvent Flux (Lm-2h-1bar-1)

Rejection (%)

Feed concentratio

n

Permeate concentratio

n

(L/mol) (L/mol)

0.9 nm 50 cm single

tube DCM 3.00 99.4 24.0 4000

Duramem-200 THF 1.01 97.26 21.6 800

Duramem-300 THF 2.03 79.4 36.6 177

Puramem-350S THF 12.0 95.6 37.0 844

Controllable addition

FeedTank

reactionvessel


Experimental results Solvent recycling and slow substrate addition with a mixer

Solvent recycling with : 50 cm Inopor 0.9 nm DM-200 Substrate dilution : 200 l/mol 500 l/mol Substrate feed tank : 25 l/mol

analysis analysis

diafiltration



Results second VID configuration • DM-200 • Mixer tank 200 l/mol • DCM

substrate product TPPO feed 1,109 0 39,34 R1 0 0,4871 20,224 R2 0 0,7535 10,165 R3 0 1,139 10,197 R4 0 1,4659 10,907 R5 0 1,5433 10,566 R6 0 1,7482 11,786 R7 0 1,6957 11,456

Permeates substrate product TPPO

P1 0 0,0068 1,245 P2 0,012 0,016 0,402 P3 0 0,0216 0,371 P4 0 0,0297 0,392 P5 0 0,031 0,394 P6 0 0,0314 0,4 P7 0 0,0316 0,412

Retentates

Rejection substrate product TPPO

P1 98,6 93,8 P2 97,9 96,0 P3 98,1 96,4 P4 98,0 96,4 P5 98,0 96,3 P6 98,2 96,6 P7 98,1 96,4

Rejections constant

Conversion 100%

Yield 66 %



Results second VID configuration • 0.9 nm TiO2 • Mixer tank 500 l/mol • DCM

Retentates

Rejection to low

name substrate product TPPO feed 0,7529 0 43,23 R1 0 0,1675 30,0003 R2 0 0,225 26,6789 R3 0,0238 0,2638 24,0592 R4 0,1263 0,2822 23,3343 R5 0,0464 0,4032 26,5557 R6 0,0587 0,3205 26,5667 R7 0,0564 0,3176 25,9881 R8 0,0539 0,3707 27,3066

Permeates name substrate product TPPO

P1 0 0 2,7039 P2 0 0,0119 2,3638 P3 0,0164 0,009 1,5248 P4 0 0,0089 2,1576 P5 0 0,0273 4,0954 P6 0 0,0092 2,4551 P7 0 0 2,5561 P8 0 0,0054 2,4803

Rejection name substrate product TPPO

P1 >99.5 91,0 P2 #DIV/0! 94,7 91,1 P3 31,1 96,6 93,7 P4 >99.5 96,8 90,8 P5 >99.5 93,2 84,6 P6 >99.5 97,1 90,8 P7 >99.5 >99.5 90,2 P8 >99.5 98,5 90,9

0

5

10

15

20

25

0 2 4 6

Yiel

d D0

1870

2 (%

)

diafiltration volumes

Yield 21 %

Reaction occurs at concentration of the storage tank (no mixing in

the mixer tank)



Results second VID configuration

PP

C26H24P2398.42

PP

O

C26H24OP2414.42

PP

O

O

C26H24O2P2430.42

P

C18H15P262.29

PO

C18H15OP278.28



Results second VID configuration • 0.9 nm TiO2 • Mixer tank 200 l/mol • DCM

Rejection phosphines 94

- > 99.5%

0 10 20 30 40 50 60 70 80

0 1 2 3 4

Prod

uct

Yiel

d (%

)

diafiltration volumes

Rejections name substrate product DPP DPPO DPPOO

P1 98,9 91,9 94,2 95,9 P2 >99.5 98,0 94,7 96,3 >99.9 P3 >99.5 97,9 95,9 96,4 >99.9 P4 >99.5 94,4 93,8 93,6 95,6 P5 >99.5 97,9 97,3 97,0 >99.9 P6 >99.5 98,2 97,6 97,3 >99.9 P7 >99.5 98,4 99,8 98,1 94,6 P8 >99.5 98,5 >99.9 98,6 92,0

Conversion 84% Yield/conversion 91%

Yield 76 %



Results second VID configuration

Yields as of batch reaction but with much lower peak volumes and solvent use

Up to 40 % reduction in PMI with unoptimized initial reactions !

0

10

20

30

40

50

60

70

80

90

0 100 200 300 400 500 600 700 800 900

Yiel

d %

Substrate concentration L/mol

DCM

THF

VID


Conclusions

New Volume Intensified Dilution Processing :

in-situ solvent recovery with OSN

+ high dilution substrate addition from low dilution feed tank

First experimental results on a macrocylization have shown :

it works !

in the two configurations suggested

yields = yields of batch reactions run at same high dilution

clear environmental benefit (PMI reduction)


Catalyst recycle: Background

•Work carried out in connection with a project concerning new functionalized ceramic membranes

•Looking at metathesis catalyst recycle via ceramic membranes.

•Several groups have looked at metathesis catalyst recyle but only with polymeric membranes.

1. Schoeps, D.; Buhr, K.; Dijkstra, M.; Ebert, K.; Plenio, H. Chemistry a European journal 2009, 15, 2960-5.

2. Keraani, A.; Renouard, T.; Fischmeister, C.; Bruneau, C.; Rabiller-Baudry, M. ChemSusChem 2008, 1, 927 - 933.

3. Keraani, A.; Rabiller-Baudry, M.; Fischmeister, C.; Bruneau, C. Catalysis Today 2010, 156, 268-275.

4. van der Gryp, P.; Barnard, A.; Cronje, J.-P.; de Vlieger, D.; Marx, S.; Vosloo, H. C. M.

Journal of Membrane Science 2010, 353, 70-77.


Catalyst recycle

COOEtEtOOCCOOEtEtOOC

Ru -cat

Molecular Formula = C13H20O4Formula Weight = 240.2955


DEDAM

CH2Cl2

ClCl

Ru

O

P


Catalyst recycle

Membrane Solvent rejection

TiO2 0.9 nm CH2Cl2 > 99%

Duramem-200 CH2Cl2 > 99.5%

Pre-catalyst Catalyst

ClCl

Ru

O

P

ClCl

Ru

P


Catalyst recycle


Catalyst recycle

0

20

40

60

80

100

120

0 1 2 3 4

%

Run

yield (TiO2)

conversion (TiO2)


Catalyst recycle

0

20

40

60

80

100

120

0 1 2 3 4

%

Run

yield (TiO2)

conversion (TiO2)

yield (DM-200)

conversion (Dm-200)


Catalyst recycle

-20

0

20

40

60

80

100

120

0 1 2 3 4

%

Run

yield (DM-200)

conversion (Dm-200)

retention dedam (DM-200)

retention product (DM-200)

retention catalyst (DM-200)


Catalyst recycle

0

20

40

60

80

100

120

0 1 2 3 4

%

Run

yield (TiO2)

conversion (TiO2)

retention dedam (TiO2)

retention produc (TiO2)

retention catalyst (TiO2)

retention catalyst (DM-200)


Catalyst recycle

Membrane Catalyst rejection (%)

Total turn over number

Turnover number

single batch DM-200 33 - 37 112

97 TiO2 77 - 82 235

HG-I reaction turnover number batchwise reaction – filter – fill system


Catalyst recycle

COOEtEtOOCCOOEtEtOOC

Ru -cat



DEDAM

CH2Cl2+

van der Eide, E. F.; Piers, W. E. Nature chemistry 2010, 2, 571–6. Demonstrated that ring closure is kinetically slightly favoured over ring opening and driven by loss of ethene.

But under pressure in a continuous system ethene can only be lost on permeation through the membrane


Catalyst recycle

0

5

10

15

20

25

30

DCM DCM no membrane


Catalyst recycle

0

5

10

15

20

25

30

DCM DCM no membrane 0

5

10

15

20

25

30

35

DCM DCM no membrane toluene 50°C

Grela, K. et al., Chemistry , 2008, 14, 806–18. Stated that increasing the temperature has more effect than increasing the catalyst loading


Catalyst recycle

0

5

10

15

20

25

30

35

DCM DCM no membrane toluene 50°C

0

10

20

30

40

50

60

DCM DCM no membrane toluene 50°C DCM 16 hrs


Catalyst recycle

Membrane Time (hrs) Solvent

DCM Tol (50°C)

TiO2 6 110 124

16 177

HG-I turnover number in continuous mode


Catalyst recycle : Conclusions

Several questions remain unanswered research in early phase Both batchwise & continuous mode give an increase in turnover number over “classic” reaction procedure Under continuous mode the membrane plays an active role in the reaction

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