Catalysis
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Metal scavenging: Development of a flow scavenging protocol
Based on a White Paper published by process chemistry specialist CatSci, this article describes the development of a flow scavenging protocol for the recovery of palladium from an optimized palladium-catalyzed Buchwald-Hartwig amination reaction.
reaction delivered the N-2 isomer of a desired pharmaceutical ingredient with >99% regioisomeric purity at the end of reaction (EOR): regulatory quality targets for the procedure required that residual palladium levels are reduced to less than 5 ppm per oral dose and less than 0.5 ppm for each parenteral administration and conducting neutral, basic or acidic washes as part of the post- reaction work-up was ineffective at removing palladium, which was found to be approximately 2000 ppm at EOR. Development of a recrystallization also proved ineffective at purging palladium.
A
n optimized palladium- catalyzed Buchwald- Hartwig amination
Furthermore, it was found that the colour of isolated N-2 was not indicative of its residual palladium content. The goal of this study was to develop a scavenging protocol that efficiently removed palladium with minimal loss of the N-2 product.
A series of scavengers (0.6 w/w with respect to N-2) were screened against EOR aliquots (1.50 mL) from a 5 g (10 vol) batch scale reaction and heated to 50°C under air over 4 hours (Figure 1). Samples were then centrifuged, and the supernatants were submitted for ICP analysis (Table 1). The three most efficient scavengers were ISOLUTE Si-TMT (entry 3, Table 1)), SiliaMetS Thiol (entry 5) and SEM26 (entry 8),
Figure 2. Scavenging efficiency against loading (4 h, 50 °C) [Pd]0 = 2654 ppm (post HCl work-up) and 1746 ppm (EOR without work-up)
reducing palladium levels by one to two orders of magnitude relative to the EOR control sample.
Figure 1. Centrifuged samples post scavenging (numbers correspond to the entries in Table 1).
Entry 1
2 3 4 5 6 7 8
32 Scavenger
EOR sample (control) DARCO KB-G ISOLUT Si-TMT SiliaMetS DMT SiliaMetS Thiol
SiliaMetS TaCOONa SiliaMetS Triamine SEM26
Optimization of the scavenging process With proof-of-concept established, further studies on these potential scavengers (Table 1) were conducted to investigate (i) mass balance or adsorption of N-2 onto the active carbon or support; (ii) the effect of work-up on scavenging efficiency; and (iii) the influence of atmosphere on oxidation of the palladium species during
[Pd] / ppm 1668
633 161 287 70
1145 656 20
Table 1 - residual palladium post-scavenging (average of two measurements).
scavenging. Activated carbons were screened under nitrogen and air where the mass loss in N-2 ranged from 18-36%; scavenging was poor and therefore further investigations with carbons were discontinued. The silica scavengers were screened under (i) a nitrogen atmosphere without work-up; and (ii) under air after an acidic work-up. The mass recovery of N-2 following treatment with the silica scavengers was superior to the carbons, ranging from 95-80%. Scavenging under air was found to be more efficient than scavenging under nitrogen in all cases, allowing for the loadings of SiliaMetS Thiol and SEM 26 to be optimized (Figure 2). Gratifyingly, the mass recovery of N-2 remained near quantitative at 50°C for both scavengers at all loadings over 4 hours. After a 24-hour period the mass recovery for SiliaMetS Thiol (0.15 w/w) had reduced to 94% while for SEM 26 it was 98%.
Scaling up scavenging
Two 10 mL samples from a 5 g (10 vol) reaction that had been
March/April 2021 • Issue 2
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