Transcript Removal of Soluble Palladium Complexes from Reaction

Palladium Removal from Reaction Mixtures by
Fixed-Bed Adsorption
M. J. Girgis1, L. E. Kuczynski2, S. M. Berberena2, C. A. Boyd2, P. L. Kubinski2,
M. L. Scherholz2, D. E. Drinkwater1, M. Yang1, X. Shen1, S. Babiak1 , S.
Farrell2, R. P. Hesketh2, and B. G. Lefebvre2
1Chemical
and Analytical Development, Novartis Pharmaceuticals Corporation, East
Hanover, New Jersey
2Department of Chemical Engineering, Rowan University, Glassboro, New Jersey
Introduction
 Metal-containing catalysts used extensively in production of pharmaceutical
intermediates and API’s
• Organometallic complexes in solution (e.g., for cross-coupling reactions)
• Supported metals (e.g., hydrogenations)
 Specifications for low metal content in drug substance (e.g., < 10 ppm for Pd for
orally administered drugs)  efficient separations processes for metals
removal needed
 Metals removal by adsorption on solids widely used in batch processes
• Solid adsorbent added to vessel
• After contacting period, adsorbent separated by filtration to give filtrate with
low metal content
• Tedious vessel cleaning required if adsorbent is comprised of fine particles
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Pd Removal by Fixed-Bed Adsorption: Concept
Clarifying
Filter
Fixed-bed with
Pd adsorbent
Pump
Reaction mixture
with large amounts of
dissolved Pd
Purified mixture
Ideally: no Pd
 Advantages over present methodology (i.e., adding fine particles to vessel)
-
Avoid vessel fouling and need for tedious cleaning, saving time and money
Avoid slurry filtration, saving one process step
Potential for adsorbent regeneration and re-use, saving disposal costs
Smaller amount of adsorbent required, reducing solid waste
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Fixed-Bed Adsorption: Principles
 Assuming liquid plug-flow
and rapid equilibrium
between liquid and solid
phases, liquid-phase
adsorbate concentration
~0 at bed exit, but rises
sharply to feed value at
breakthrough time, given
by:
tbrkthru
L   B q0* 
 1 
v
 c0 
tbrkthru  breakthrough tim e
L  length of fixed bed
v  fluid interstitial velocity
 B  m ass of solid adsorbent/ bed volum e
  bed void fraction
c0  feed m etalsconcentration
q0*  solids m etalsconcentration in equilibrium with feed liquid
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Objective and Approach
 Objective: devise methodology allowing estimation of breakthrough time for
fixed-bed adsorption applied to the removal of soluble organopalladium
complexes
 Approach: use an actual reaction mixture (representative of those encountered
in practice) to characterize adsorption and evaluate fixed-bed performance
 Heck coupling selected as a representative reaction
O
O
HC
HC
Pd(OAc)2
P(o-Tol)3
O
+
CH 3
+
+
Bu3N
Bu3N . HBr
CH3CN
O
Br
O
O
CH 3
1
2
3
 Adsorption characterized in presence of other species (e.g., reaction product,
catalyst, solvent, reagents) which could impact adsorption
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Chemical Reaction
Procedure
 Conducted based on procedure developed in-housea, and performed typically
on 600-mL scale using jacketed vessel with overhead agitation
• Charge: 183 g of aldehyde 1 (989 mmol), 1.11 g of Pd(OAc)2 (5 mmol), 6.02 g
of P(o-Tol)3 (20 mmol), 467 g of CH3CN (594 mL), 189 g of Bu3N (1.02
mmol), and 87.9 g of olefin 2 (1.02 mmol)
• Heat reaction mixture to 75 °C over 20 min and hold for at least 16 h
 Untreated final reaction mixture contains about 560 ppm Pd, isolated solid 3
contains about 2100 ppm Pd  suitable reaction for investigating Pd-removal
O
O
HC
HC
Pd(OAc)2
P(o-Tol)3
O
+
CH 3
+
+
Bu3N
CH3CN
O
Br
aSlade,
O
J. and Liu, H. personal communication
O
CH 3
1
2
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3
Bu3N . HBr
Batch Adsorption Experiments
Procedure
 Apparatus: six constant-temperature small baths, each with independent
temperature and agitation control
 Vials containing 15-20 mL of Heck coupling reaction mixture placed in each
bath, with varying amounts of adsorbent (0.025-2 g) added to each vial
 Slurries agitated with magnetic stir bars overnight to allow equilibration, with
vials sealed to minimize solvent loss (material balance closure typically > 95%)
 Solids filtered, filtrates analyzed for Pd content using ICP/OES (Robertson
Microanalytical Laboratories, Madison, NJ), solid-phase Pd content calculated
by difference
 Three adsorbents investigated: (a) P1400 activated carbon (PICA), (b) Smopex
110, comprising thiourea grafted polyolefin fiber (Johnson Matthey) and (c)
QuadraPure TU, consisting of thiourea bound to 0.5-mm resin beads (Reaxa
Ltd.)
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Adsorption Isotherms
at Room Temperature
Equilibrium Isotherms at Room Temperature
10000
Quadrapure TU
Solid Phase Pd conc, wPPM
9000
Activated Carbon
8000
Smopex
7000
6000
5000
4000
3000
2000
1000
0
0
100
200
300
400
500
600
Liquid Phase Pd conc, wPPM
 QuadraPure TU has significantly higher capacity for Pd than Smopex and
PICA-P1400 activated carbon and selected for subsequent experiments
 Isotherms can be used as adsorbent quantitative ranking tool
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Adsorption Using QuadraPure TU at Higher Temperature
20000
60 °C
Solid-phase Pd Concentration, ppm
18000
16000
14000
12000
10000
40 °C
8000
6000
25 °C
4000
2000
0
0
50
100
150
200
250
300
350
Liquid-phase Pd Concentration, ppm
Greater Pd-removal capacity at higher temperature
 Isotherms can also be used to select optimal adsorption temperature
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400
Fixed-Bed Experiments: Apparatus
Outlet
Jacket
RTD Probe
Quadrapure bed
(diluted with glass beads)
Glass beads
Inlet
Detail of fixed-bed
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HPLC Method for Pd Detection
 Sodium diethyldithiocarbamate (Na-DEDTC) forms complexes with Pd species
in solution with good UV absorption
S
N
SNa
 Structure of complex unknown, but may involve coordination of 1 Pd cation with
2 DEDTC anions
 Sample preparation:
• 0.1 mL of reaction mixture
• 0.1 mL of Na-DEDTC solution
• 0.5 mL of acetonitrile
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Initial Runs: Fixed-Bed Adsorption Experiments with QuadraPure TU
 Vendor recommendations (Hinchliffe et al., Org. Proc. Res. Dev., 11(3), 2007,
477)  flow rate of 4-6 column volumes/h
 More conservative value of 1 column volume/h used in initial runs
 Vendor-specified resin capacity of 20 mg Pd/g resin and 570 ppm Pd feed
content  resin mass used (2.4 g) should process 107 mL of reaction mixture,
giving tbrkthru = 5.9 h at flow rate employed (0.3 cm3/min)
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Initial Runs: Fixed-Bed Adsorption Experiments with QuadraPure TU
Representative Results
3.5E+03
100
Relative Pd Concentration by HPLC
HPLC/UV
90
ICP/OES
80
2.5E+03
70
60
2.0E+03
50
1.5E+03
40
30
1.0E+03
20
5.0E+02
Pd concentration from ICP/OES, ppm
3.0E+03
10
0.0E+00
0
0
1
2
3
Time, h
4
5
 Actual tbrkthru < 2 h << predicted value of 5.9 h
 Good Pd removal performance: samples (up to 2.55 h) combined, giving 6 ppm
of Pd in liquid mixture and 24 ppm in isolated product
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First Hypothesis for Poor Column Performance: Axial Dispersion
Toluene Tracer Experiments
 Axial dispersion was
found to be minimized
with:
•
Small glass beads
(0.5 mm)
•
Undiluted bed (pure
resin)
 No significant impact of
flow rate on axial
dispersion in flow-rate
range examined
 Decreased axial
dispersion did not
increase breakthrough
time  axial dispersion
unlikely to cause poor
column performance
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Second Hypothesis for Poor Column Performance: Insufficient
Equilibration Time
Time-to-Equilibrium Experiment
Time to Equilibrium Experiment
160
Reaction Mixture
Pd Acetate in CH3CN
Pd concentration (ppm)
140
120
100
80
60
40
20
0
0
2
4
6
8
10
time (hours)
 ~ 6 h required to reach equilibrium between resin and reaction mixture
 Bed residence time in initial experiments < 30 min  equilibrium apparently not
reached
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Adsorption Experiment with 2-h reaction time
Design Procedure
M
Q   res
 B
Inputs
tres
2h
Mres
17.3 g
B
0.501 g/cm3

0.400
A
1.69 cm2
c0
570 ppm
q0*
18,000 ppm
L
 

 t res



M re sin /  B
A
v
L = 20.5 cm
Q
A
v = 10.2 cm/h
v
v* 
1
B q
 c0
t* 
*
0
L
v*
Q = 6.91 cm3/h
v* = 4.24 x 10-3 cm/h
t * = 80.3 h
*
Volume processed at t = 560 cm3
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Adsorption Experiment with 2-h reaction time
Column Run 0702 - Breakthrough (HPLC)
4.5
Breakthrough
4.0
Pd Concentration (ppm)
3.5
3.0
2.5
2.0
55.33 h, decreased
flowrate 0.09
mL/min
1.5
1.0
0.5
0.0
0
10
20
30
40
Time, h
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50
60
70
80
Adsorption Experiment with 2-h reaction time
Performance Table
Run 2
Expected Breakthrough (h)
80.3
Actual Breakthrough (h)
70.6
Efficiency h
0.88
Mass Treated (g)
369
Mass of Resin (g)
17.3
S/L
0.044
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Adsorption Experiment with 2-h reaction time
Product Recovery
Crop 1 Mass (g)
Crop 1 Concentration (ppm)
Crop 2 Mass (g)
Crop 2 Concentration (ppm)
Run 2
56.2
3
9.44
9
Weight Average Concentration
(ppm)
3.86
Yield (%)
67.9
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Tradeoff of Efficiency with Bed Residence Time
Residence Time vs. Efficiency
1.0
0.9
0.8
0.7
h
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.0
0.5
1.0
1.5
Residence Time, h
 Efficiency flattens near bed residence time of 1 h
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2.0
2.5
Design Procedure
 Breakthrough time given by modified equation:
tbrkthru
L   B q0* 
 h 1 
v
 c0 
• Efficiency h determined experimentally
 Equation above implies:
tbrkthru
L/v

plant
tbrkthru
L/v
lab
 If same breakthrough time is desired on large and small scales, large-scale
column operating parameters are given as follows to process a volume V of
solution:
Q
V
tbrkthru
M res 
Q B

L
M red /  B
A
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Comparison of Resin Requirements vs. Batch Adsorption
 = 1.25-h residence time case
 310 g of solution treated with 17.3 g of resin  S/L = 0.0558 g/g
 Using isotherm and mass balance, Pd removed using batch adsorption at the
same S/L can be estimated
800
700
ppm of Pd in liquid
600
500
400
300
200
S/LL = 0.055
100
0
0
2000
4000
6000
8000
10000
12000
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ppm of Pd on solid
14000
16000
18000
20000
Comparison of Resin Requirements vs. Batch Adsorption
 = 1.25-h residence time case
 Single batch adsorption stage at S/L = 0.0558
• 15 ppm of Pd for the liquid-phase palladium concentration (estimated: 55 ppm
for solid)
 To obtain a Pd content of 7 ppm in the isolated solid (or 1.9 ppm in the liquidphase reaction mixture) with a single batch adsorption stage
• S/L value of 0.24 required
• Corresponds to 4.3 times resin required in the fixed-bed with 1.25-h residence
time and 72% efficiency
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Conclusions
 Adsorption of soluble palladium species characterized quantitatively by
determining adsorption isotherms for three adsorbents
 Adsorption isotherms used to select best adsorbent (QuadraPure TU) and
optimal adsorption temperature (60 °C)
 Short breakthrough times in initial fixed-bed experiments attributed to
insufficient approach to equilibrium
 Experiments with bed residence times giving closer approach to equilibrium
gave bed performance > 70% of the theoretical degree of palladium removal
based on the assumption of local fluid-solid equilibrium
 Design methodology developed in which actual tbrkthru estimated from
experimental determination of bed efficiency vs. residence time
 To obtain the same extent of palladium removal, fixed-bed adsorption requires
<25% the resin amount relative to a single stage of batch adsorption
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Acknowledgments
 Dr. Joel Slade, Dr. Hui Liu, and Mr. Mark Davis for consultations and assistance
with the Heck coupling reaction
 Dr. Mahavir Prashad for advice on adsorbent and reaction selection
 Mr. Lee Alden for assistance with design and construction of experimental
apparatus
 Drs. Thomas Blacklock and Oljan Repič for management support
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