Identification and Elimination of an Unexpected Catalyst Poison in

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Identification and Elimination of an Unexpected Catalyst Poison in Suzuki Coupling Jing Liu, Kyle Kimmel, Kimkim Dao, Yang Liu, and Ming Qi Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00342 • Publication Date (Web): 08 Dec 2017 Downloaded from http://pubs.acs.org on December 9, 2017

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Organic Process Research & Development

Identification and Elimination of an Unexpected Catalyst Poison in Suzuki Coupling Jing Liu*†, Kyle Kimmel‡, Kimkim Dao†, Yang Liuǁ, Ming Qi# † Dart NeuroScience, L.L.C., 12278 Scripps Summit Drive, San Diego, CA, 92131 ‡ Current address: Intercept Pharma, 4760 Eastgate Mall, San Diego, CA 92121 ǁ Accela ChemBio Ltd, 222 Guangdan Road, Building 21, Shanghai, 201318, China # Current address: Zinnova Co. Ltd., 780 Cailun Rd, Suite 821, Shanghai 201203, China

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FOR TABLE OF CONTENT


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KEYWORDS: Suzuki coupling, catalyst poison, elemental sulfur, GMP manufacturing

ABSTRACT

A Suzuki coupling reaction gave an uncharacteristically low conversion in a GMP campaign. Initial investigation revealed a Palladium catalyst poison in the starting material. A temporary solution was developed along with contingency plans to enable successful material delivery. Further systematic studies led to the identification of elemental sulfur as the culprit. A ‘sulfurfree’ synthesis of the starting material was developed for the next round of manufacturing.


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INTRODUCTION Transition metal-mediated cross coupling reactions such as Suzuki-Miyaura couplings are among the most popular chemistry tools for drug discovery,1 since they offer direct access to biaryl systems that are ubiquitous in modern day drug candidates. However, in process chemistry R&D, these cross coupling reactions often present unique challenges.2 The main concerns are often robustness, scalability, and heavy metal contamination. In particular, catalyst poisoning often becomes a more prominent issue due to the lower catalyst loadings typically employed in large scale manufacturing.3 For one of our projects, biaryl intermediate 1 was needed on multi-kilogram scale. We developed a convenient telescoped process that includes the methoxylation of nicotinate 2 followed by one-pot Suzuki coupling (eq 1). The sequence uses readily available starting materials along with an inexpensive and stable palladium source and ligand at low loading. More importantly, it gave very consistent and excellent results throughout the process R&D phase, from milligram to kilogram scale. Therefore, we applied it in the first round of GMP manufacturing (campaign 1) and obtained good results as expected on > 6 kg scale.

We then carried out a second GMP synthesis (campaign 2) on similar scale using identical procedures, with new batches of materials from the same suppliers. Unexpectedly, while the


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methoxylation step went to completion, subsequent coupling gave almost no desired compound 1. The main product was 3, resulting from the hydrolysis of intermediate 4 (Scheme 1). A thorough investigation was conducted, and the detailed results are discussed herein. Scheme 1. Unsuccessful Suzuki Coupling in GMP Campaign 2.

RESULTS AND DISCUSSION 1) Initial Investigation We first conducted stress studies to see if the cross coupling step was sensitive to air, moisture, or stoichiometry of reagents. Interestingly, the reaction proved to be very robust in most cases. The only stress test that gave a similar profile as observed in GMP campaign 2 was when Pd(OAc)2 catalyst was intentionally omitted. The possibility of operator human errors in GMP campaign 2 was quickly ruled out, which leaves palladium catalyst poisoning as the likely problem. Next, a systematic testing of all starting materials and reagents was performed to see if the issue could be attributed to a defective batch of material. The tests were done using batches of materials that were known to give good reactions in R&D or GMP campaign 1, substituted one


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at a time with the batch used in the unsuccessful GMP campaign 2. All use tests gave complete conversion, except the one using the new lot of nicotinate starting material 2. Therefore, we suspected that the new lot of 2 contained a new impurity that poisoned the palladium catalyst. This lot of 2 was then analyzed by 1H/13C-NMR, HPLC-MS, and CHN elemental analysis. It showed very high purity, and the impurity profile was practically identical as previous ‘good’ lots. The material vendor was unwilling to disclose their manufacturing process, but did inform us that SOCl2 was used. However, no sulfur was detected by sulfur elemental analysis. While further troubleshooting was still underway, we needed to restart the GMP campaign to meet the original material delivery goal. Therefore, a purification protocol was developed to remove the unidentified catalyst poison (Scheme 2). Nicotinate 2 was first dissolved in MTBE and washed with water to hydrolyze any potential residual SOCl2 and remove any water-soluble impurities that might be present. It was then recrystallized from heptane.4 At this stage, a use test was the only way to test the effectiveness of the purification. On 100 g scale, the Suzuki coupling step worked very well with the original 0.5% catalyst loading. Scheme 2. Purification of Nicotinate Starting Material 2


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While the good use test result provided some assurance, several contingency plans were also developed to ensure a successful GMP production. We found that a stalled Suzuki coupling could almost always be ‘revived’ if enough additional catalyst and ligand were added. It was also important to detect the stalling as early as possible to prevent the hydrolysis of intermediate 4. The coupling step was typically completed within 2-4 hours if no catalyst poison was present. On the other hand, hydrolysis of 4 usually became significant 6-8 hours after the reaction had stalled. Based on the data, additional in-process controls were implemented to detect stalling within 1-2 hour. Additional catalyst and ligand (up to 5%) would be added if stalling was detected. The exact amounts to be added would be calculated based on the conversion at the time. It should be noted that although increasing catalyst loading might appear to be a simple solution, it would lead to other issues downstream. We found that higher catalyst loading significantly increased the residual Pd level in product 1, which in turn negatively impacted subsequent reactions. A screening study was carried out to investigate the removal of residual Pd in 1. The optimal conditions were found to be Si-Thiol metal scavenger in toluene, which reduced the Pd level to below 200 ppm. This procedure was planned as an optional step that would be performed if additional catalyst was added. With a purified starting material, a successful use test, and multiple contingency plans in hand, we restarted the GMP campaign two months after the initial incident. The Suzuki coupling gave higher conversion than before, but stalled prematurely again with the original 0.5% catalyst loading. Fortunately, the contingency plans worked well. The problem was detected in a timely fashion by in-process controls. Addition of more catalyst (1.5%) and ligand (3%) led to complete conversion. Product 1 was isolated in 73% yield with 98% purity. The subsequent Pd


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removal step was carried out as planned, and the remainder of the GMP synthesis proceeded well to provide final API in the desired quantity and purity. 2) Identification of Catalyst Poison While we achieved the immediate material delivery goal, the purification procedure alone was clearly not enough to guarantee a successful reaction. It was imperative to identify the catalyst poison and develop a control strategy. First, we revisited the possibility of SOCl2 as the culprit. We spiked a known good lot of starting material 2 with SOCl2. The Suzuki coupling use test indeed failed. However, when the spiked lot was purified per the procedure in Scheme 2, the coupling gave complete conversion. This showed that even if SOCl2 were present in 2, it would have been effectively removed during the purification that included an aqueous wash. Therefore, SOCl2 was not the catalyst poison. We also examined and ruled out several possible derivatives of SOCl2, such as SO(OMe)2. Next, we focused on the isolation of the catalyst poison. During the purification (Scheme 2), the mother liquor was concentrated to give batch ML1. It is likely that this batch contained increased level of catalyst poison.5 However, 1H-NMR, GCMS, and CHN elemental analysis still showed very high purity. Therefore, we decided to process batch ML1 through two more heptane recrystallizations in the hope to further enrich the catalyst poison in the mother liquor (Scheme 3). This gave batches R2, ML2, R3, and ML3. Scheme 3. Enrichment of Catalyst Poison


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We then performed use tests on all five batches. Catalyst and ligand were dosed in increasing portions and IPCs were taken 1 hour after each dose.6 All reactions gave low and varying conversions at the original 0.5% catalyst loading. Additional catalyst and ligand were dosed in increasing amounts, and eventually all reactions went to completion at various higher loadings (Table 1). The five batches were also tested for sulfur content. Interestingly, sulfur was now detected in all batches, and the amount of sulfur directly correlated to the amount of Pd catalyst needed for complete conversion.7 These results clearly demonstrated that the catalyst poison contains sulfur, and was enriched in the mother liquors through successive recrystallizations. Table 1. Correlation of Use Test Results and Sulfur Content Batch

Pd(OAc)2 needed

Sulfur content (wt%)

ML1

10%

2.65

R2

5%

1.36

ML2

15%

7.01

R3

20%

9.87

ML3

15%

6.58


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Based on the data, we suspected that sulfur was actually present in the initial batch of 2 as well, but below the detection level of elemental analysis (0.2%). Therefore, we tested the batch by a much more sensitive method, sulfur ICP-OES. Indeed, it was found to contain 0.13% of sulfur, which is just below the sensitivity of conventional sulfur elemental analysis. Finally, the batch of 2 used in the successful GMP campaign 1 was found to contain very little sulfur (19 ppm, or 0.0019%), further confirming the correlation between sulfur content and catalyst poison. Next, we proceeded to isolate and identify the catalyst poison from batch R3, which has the highest sulfur content (Table 1). While no significant impurities were observed by NMR or HPLC, a very non-polar but UV active impurity was seen on TLC. The impurity was isolated by silica gel column chromatography as a light yellow solid. When it was spiked into a ‘clean’ batch of 2, the Suzuki coupling failed. This confirmed that the isolated compound was indeed a catalyst poison. The isolated catalyst poison was then characterized by 1H/13C-NMR and HPLC-MS. We were initially puzzled by the complete absence of NMR and HPLC signals.8 However, the GC-MS spectrum showed the distinctive pattern of elemental sulfur (S8).9 The Rf value for TLC also matched that of elemental sulfur reference standard. To confirm that S8 can indeed poison the Suzuki coupling, we spiked a ‘clean’ batch of 2 with increasing amount of S8 and conducted use tests (Table 2). The correlation between the amount of S8 and amount of catalyst required is almost identical with that observed previously in Table 1, further confirming the identity of the catalyst poison.


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Table 2. Correlation of Amount of Spiked Elemental Sulfur and Required Catalyst Loading Sulfur Spiked

Pd(OAc)2 Needed

None

0.5%

0.2%

1%

1%

5%

10%

25%

Finally, our observations during the purification of 2 could be explained well with S8 as the catalyst poison. Dissolution in MTBE and water wash would do little to remove elemental sulfur, but heptane recrystallization could remove S8 to some extent due to its limited solubility in heptane.10 Based on the above results, the Pd catalyst poison present in nicotinate starting material 2 was positively identified as elemental sulfur. 3) Origin of Catalyst Poison The identification of elemental sulfur as catalyst poison solved one puzzle, but immediately generated another. How could compound 2 be contaminated with S8, when sulfur was unlikely to be used in the synthesis? We initially thought this could be a one-time accidental contamination. To test this hypothesis, commercial supplies from seven major vendors were surveyed for sulfur content. Rather unexpectedly, five out of seven batches contained various levels of sulfur (Table 3). To eliminate interference from SOCl2 (likely used in synthesis), the five batches were purified by aqueous washes and analyzed again. The sulfur content did decrease in most batches, but still remained at a significant level. Suzuki coupling use tests of


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several batches were carried out, and the results corresponded well with the measured sulfur contents. Table 3. Sulfur Content in Commercial Supplies of 2 Sulfur Content1 Vendor As received

After H2O wash

A

0.18%

0.18%

B

0.52%

0.22%

C

0.83%

0.66%

D

1.86%

0.37%

E

0.65%

0.34%

F

Not detected2

Not tested

G

Not detected

Not tested

1.

By elemental analysis, detection level 0.1%

2.

10 ppm by ICP-OES

The above results clearly indicated that sulfur contamination was not an isolated incident as we initially hypothesized, but a rather common phenomenon.11 Therefore, it is likely related to the prevailing manufacturing process. While none of the suppliers were willing to disclose their exact route, it is probable that nicotinic acid 5 was used as a precursor.12 Commercial supplies of 5 were examined for sulfur content, and this time no sulfur was detected at all. Therefore, we believe that elemental sulfur was introduced during the transformation of 5 to 2, most likely in the esterification step involving SOCl2.


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Based on the literature, we believe that elemental sulfur could be generated from the reaction between SOCl2 and DMF, a reagent combination commonly used for esterification. The wellknown reaction between SOCl2 and DMF gives the Vilsmeier reagent. However, SOCl2 is known to decompose to SO2Cl2 and SCl2, and the latter can react with DMF to generate dimethyl carbamoyl chloride (DMCC), along with sulfur as the stoichiometric byproduct (Scheme 4).13,14 SCl2 might also be a process impurity in SOCl2, since it is commonly used in the commercial production of SOCl2.15 Scheme 4. Formation of Elemental Sulfur from SOCl2 and DMF

Very interestingly, Tian and workers investigated the formation of DMCC from SOCl2 and DMF and found that pyridine accelerated the reaction by ~1,000 fold.11 This could certainly be a factor in our case, where the substrate is a pyridine. To test whether sulfur can indeed be formed in our reactions of interest, we carried out the esterification of both acids 5 and 6 with excess SOCl2/DMF (Scheme 5). Interestingly, the isolated products in both reactions (2 and 7) contained significant amount of sulfur (1.9% and 6.8% respectively).16 These results confirmed that formation of elemental sulfur is indeed possible under the reaction conditions. Scheme 5. Sulfur Content in Products from Esterifications Using SOCl2/DMF.


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4) New Synthesis of Nicotinate Starting Materials It became clear that to avoid sulfur contamination completely, we needed an alternative synthesis that does not involve SOCl2/DMF. We would also like to develop a more scalable route that can lower the cost of goods, because compound 2 is one of the more expensive starting materials in the overall synthesis. To this end, we developed the route depicted in Scheme 6. Scheme 6. ‘Sulfur-Free’ Synthesis of Nicotinate Starting Materials 2 and 4


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The first step is the bromination of readily available 6-hydroxynicotinic acid (8). Among the brominating reagents screened, bromine in acetic acid gave the best results. Nicotinic acid intermediate 5 was then doubly chlorinated with POCl3 or triphosgene. The resulting acid chloride 9 was quenched with methanol in a one-pot fashion to afford 2. While 2 could be easily isolated at this stage, we decided to telescope the process further to give advanced intermediate 4 via a one-pot methoxylation. Final product 4 was recrystallized from MeOH/water in high yield and purity. We plan to use compound 4 instead of 2 as the starting material for future GMP campaigns. We transferred this route to our CMO partner, who made further fine optimizations and manufactured 4 on kilogram scale. As expected, the product contained no sulfur (

Identification and Elimination of an Unexpected Catalyst Poison in

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