Impact of Lead Impurities in Zinc Dust on the Selective Reduction of a

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Impact of Lead Impurities in Zinc Dust on the Selective Reduction of a Di-Bromoimidazole Derivative Jianguo Yin, Courtney K. Maguire, Nobuyoshi Yasuda, Andrew P. J. Brunskill, and Artis Klapars Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00370 • Publication Date (Web): 08 Dec 2016 Downloaded from http://pubs.acs.org on December 15, 2016

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Organic Process Research & Development

Impact of Lead Impurities in Zinc Dust on the Selective Reduction of a DiBromoimidazole Derivative Jianguo Yin,* Courtney K. Maguire,* Nobuyoshi Yasuda, Andrew P. J. Brunskill and Artis Klapars Department of Process Research & Development, Merck Research Laboratories, Rahway, New Jersey 07065, USA

[email protected]; [email protected] RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)

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TOC Graphic

Bulk Zn

Agglomerated Zn post rxn

Zinc before (left) & after (right) rxn


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Abstract: A low level of lead in zinc dust was identified as the causative agent responsible for inhibiting selective reduction of a di-bromoimidazole derivative via metal agglomeration and lead deposition on the zinc surface.

Keywords: Zinc reduction, metal contamination, Elbasvir, Zepatier, metal agglomeration



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Introduction

Zinc is a versatile reagent in organic transformations.1 When used as a reducing agent, it is also often a favorite choice for the process chemist since it is readily available and inexpensive2. However, trace amounts of other metal impurities, especially lead, in zinc can have a profound impact on its reactivity. The improvement of reaction efficiency resulting from trace amounts of lead in zinc dust has been reported for a Wittig-type olefination using a zinc carbenoid3, and for a thiocarbonyl reaction using zinc.4 However, lead as an impurity has been found to inhibit the Simmons-Smith cyclopropanation

or the conversion of alkyliodides to alkylzinc reagents.5

When the impact of metallic impurities on the reaction rate is negative, such impact can often be overlooked, as diminished reactivity can usually be overcome through the use of excess reagent with little impact to the cost of goods. Elbasvir (1) is one of the active pharmaceutical ingredients in the once-daily HCV treatment Zepatier.TM 6 The synthesis of elbasvir required the use of N-Boc imidazole mono bromide 3 as a double Suzuki-Miyaura cross coupling partner to the boronate ester 27a-c (Scheme 1). Scheme 1. Preparation of Elbasvir. N

O

N

N Boc HN

O B

O B N

O O

Ph

3

Br

N H

N

N

O

N O

NHCO2Me

Ph

N H O

N

1

2 Elbasvir

MeO 2CHN

A cost-effective and reliable synthesis of the mono-bromide 3 is therefore important. As reported previously, selective reduction of the N-Boc dibromo imidazole derivative 5 by zinc metal was developed as the enabling route to make this intermediate.7c During the course of process development, it was discovered that a commercial supply of zinc dust was extraordinarily less effective for the reduction reaction. The impact was initially ignored since the use of excess zinc


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could mitigate an incomplete conversion. Additional studies, discussed herein, identified the root cause of low reactivity was trace lead content in zinc dust.

Results and Discussion The dibromide 5 was easily accessible through the bromination of N-Boc imidazole 4 as reported previously.7c Though a variety of methods for arylhalide reductions have been reported, the primary focus was on the use of zinc dust in aqueous methanolic solution as these conditions afford a cost-effective and practical system (Scheme 2). Initial optimization revealed a particular sensitivity of the reaction to pH. In a reaction medium with pH values less than 8, unproductive consumption of zinc metal was observed, presumably due to hydrogen gas generation. At pH values greater than 10 a noticeably slower reaction was observed. The optimized reaction employed EDTA, ammonium hydroxide and zinc dust in a MeOH/water mixture at 40oC, which maintained a pH of approximately 9. Under these conditions complete consumption of 5 occurred in 1.5 h using 1.3 equivalents of zinc, with formation of 5 mol % over-reduction product 4. A simple extractive protocol was developed which rejected 4 to the aqueous phase during workup, ultimately providing 3 in 86% yield and >99% purity.

Scheme 2. Optimized Reaction Conditions for Selective Reduction of Dibromide 5 N N Boc 5

Br

N H

Br

MeOH/H 2O 1.2 equiv. EDTA 2.7 equiv. NH4OH 1.3 equiv. Zn 40 oC, 1.5 h

N

N N Boc

+

N H

Br

N Boc

3

N H 4

3 : 4 = 94%: 5%

When the optimized reaction conditions were employed using one of the commercial sources of zinc dust, a severe retardation of the reaction rate occurred. Agglomeration of zinc



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metal occurred, and only 40% conversion was observed after a few hours using the optimized zinc charge of 1.3 equivalents. The reaction could be pushed to completion, but only through charging additional zinc (1.7 equiv. total) and buffer solution over a day. To determine the root cause of this irreproducibility and devise a robust procedure for this transformation, a thorough investigation was initiated. Various lots of zinc metal from multiple commercial suppliers were procured, characterized and evaluated for performance in the reduction reaction (Table 1).8 The results for the zinc metal used in the initial optimization experiments (Zinc A) are shown in entry 1. Additional lots of zinc from this supplier showed similar purity and specific surface area (SSA), and performed well in the reduction reaction. The reaction gave greater than 95% conversion in one hour. The effect of metal SSA on the reaction was evaluated (Table 1, Entry 4) and it was found that even with a 34x decrease in SSA the reduction reaction was not impacted. The zinc dust from the bulk supply (Zinc B) showed markedly different analytical results (Table 1, Entry 5). The material displayed a significantly larger SSA (0.7513 m2/g), and showed high levels of trace metal impurities, including iron (920 ppm) and lead (2,390 ppm or 0.07 mol% on the basis of zinc).9 These data suggested the sluggish reaction observed using the bulk supply of zinc dust was due to the higher metal impurities, especially lead. A visual comparison of the zinc dust before and after the reaction is shown in Figure 1, highlighting the agglomeration that was observed. Table 1: Analysis and Reactivity of Zinc Metal from Different Suppliers

Entries

Zinc Dust/Powder

Purity* (%)

Specific Surface Area (SSA) (m2/g)**

Metal Impurities (ppm)**

Reaction Conversion (%)#

1

Dust (Zinc A)

98

0.1960

Cu: 28

>95

2

Dust

98

0.2288

Cu: 35

>95


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3

Dust

98

0.2318

Cu: 77; Fe: 32

>95

4

Powder

99.9

0.0068

Cu: 50

>95

5

Dust (Zinc B)

98

0.7513

Cu: 50; Fe: 920; Pb: 2390

37

6

Powder

99.9

ND##

In: 40; Pb: 65

84

7

Dust

98

ND##

Pb: 10

86

*Purity as shown on vendor certificate of analysis; **Analytical data generated in this work; if an element is not listed, the level was undetectable; #The conversion of reduction reaction with 1.3 eq. of zinc after 1h at 40 o

C; ## Not determined.

a)Zn dust before the reaction b)Agglomerated Zn residue c)Side by side comparison of (250X)

from the reaction (25X)

Zn dust before and after reaction

Figure 1. a) SEM Images of zinc dust and b) agglomerated zinc; c) Visual comparison of zinc dust and agglomerated zinc

In general, an empirical trend was noted between the level of trace metal impurities in the bulk zinc, particularly lead, and conversion in the reduction reaction. Even high quality zinc powder (99.9%) which contained only 65 ppm lead resulted in a lower conversion (entry 6). Standard methods for activation of zero-valent metals (pre-treatment with acid or TMSCl) did not return the reaction to typical conversion when trace metal impurities were present. Having



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ruled out zinc surface area and activation as root causes for poor performance in the reduction, an investigation into the observed empirical correlation of trace metal impurities with low reactivity was pursued. A series of spiking experiments using lead powder10 were performed (Table 2). The control experiments using zinc A and B showed 100% and 50% conversion respectively as expected after 3 h (entries 1 and 2). Addition of 9.1 wt% lead powder to zinc A led to only 30% conversion after 3 h (entry 3) at which point the reaction was essentially stalled and metal agglomerates were observed. Decreasing the lead amount 10 and 40 fold (corresponding to 0.91 wt% and 0.24 wt% of lead) resulted in improved but still incomplete conversions in both cases (entries 4 and 5). Comparing the results in entry 2 and entry 5, the rate retardation observed by addition of 0.24 wt% of lead powder to zinc A was much less severe than that observed using zinc B containing the similar amount of lead. A probable cause is better dispersion of lead in zinc B. Nevertheless, these spiking experiments clearly demonstrated that lead in zinc dust was likely the root cause of the metal agglomeration and consequently lower conversion in the reduction reaction.


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Table 2 Impact of Lead on Reaction Conversion

Entry Zn dust Lead added (wt %)

Reaction Conversion (%) 1h

2h

3h

Metal Residue

Filtrate

1

Zinc A

None

95%

100%

---

Zn: 98% Pb: 129 ppm

Zn: 2.7%

2

Zinc B

None

37%

44%

50%

Zn: 80% Pb: 5.6%

Zn: 2.3% Pb: 35 ppm

3

Zinc A

9.1%

28%

29%

30%

Zn: 89%; Pb: 11%

Zn: 1.2% Pb: 60 ppm

4

Zinc A

0.91%

74%

79%

80%

Zn: 96% Pb: 3.9%

Zn: 2.3%

5

Zinc A

0.24%

89%

92%

93%

Zn: 98%; Pb: 2.2%

Zn: 2.5%

It is hypothesized that due to the difference in oxidation potential between zero valent zinc and lead,11 only the former is competent to engage the imidazolyl bromide in a single electron transfer reduction. As such, it was expected that after the reaction any recovered metal should be enriched in lead, with the soluble zinc(II) by-product being removed to the solution phase. Indeed this proved to be the case (Table 2), and for all reactions where lead was added, a significant lead wt% enrichment in the recovered metal was found (entries 2-5). In order to confirm lead was completely inactive in the reduction reaction, a separate reduction experiment was carried out using 2.0 equiv. of lead powder (200 mesh, 99%) as the reducing agent. After the reaction mixture was heated for 2 h at 40 oC, no reaction was observed and 100% lead metal was recovered. In addition, the lead powder quickly agglomerated, as is clear from a visual comparison of the lead powder charged to and recovered from the reaction (Figure 2).



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a)

Pb

(250X)

powder

as

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received b) Pb agglomerates observed c) Side by side comparison under reaction conditions (25X)

of

Pb

powder

agglomerates

and

before

after reaction Figure 2 a) SEM image of Pb powder as received, b) SEM image Pb balls observed under reaction conditions, and c) Visual comparison of Pb powder and Pb ball before and after reaction.

From the data collected it was clear that the formation of metal agglomerates was caused by a higher lead content in the zinc dust. Despite the fact that the reduction reaction could proceed using zinc of varied surface area (Table 1, entry 3 and 4), a drastic reduction in surface area caused by agglomeration could still be the major reason for a stalled reaction by preventing physical contact of zinc metal with the reaction medium. To further interrogate this hypothesis, residual zinc isolated from experiment 3 in Table 2 was isolated, ground with a mortar and pestle, and then returned to the reaction mixture and heated. This second reaction then proceeded another 20%, after which the reaction again stalled and the zinc was visibly agglomerated. Surface area is one of the critical attributes involved in the reaction and agglomeration of metal particulates. To characterize the surface metal composition at the end of the reduction reaction, X-ray Photoelectron Spectroscopy (XPS) analysis was performed (Table 3).


Pb and

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Table 3 XPS Analyses of Zn Dust Surface Before and After the Reduction (weight %) Entry 1 2

Sample C N O Zn Br Pb 18.7 0.0 45.1 36.2 0.0 ND Zinc A 23.3 0.0 43.1 32.7 0.1 0.9 Zinc B Filtered residual metal 3 30.5 6.2 37.7 24.2 1.1 0.3 from Zinc A Filtered residual metal 4 46.2 8.5 30.6 11.2 2.4 1.2 from Zinc B The results suggest that coating of zinc metal surface by lead took place during the reaction. For example, as shown in Table 4, the lead content on the surface of zinc B before the reaction was 2.7% on the basis of zinc (entry 2). When the reaction stalled, the residual metal was separated from the reaction mixture and the weight of the recovered metal was reduced by about one third. The Pb content on the recovered metal surface was only expected to increase proportionally. However, the recovered metal residue from the reaction showed a surface lead content of 10.7% on the basis of zinc, as shown in entry 4, conclusively demonstrating deposition of lead on the alloy surface. Table 4. Comparison of Surface Enriched Lead to Zinc Ratios Before and After Reaction Entry 1 2

Sample Zinc A Zinc B

Lead/Zinc Ratio Before Reaction ND 2.7%

Lead/Zinc Ratio After Reaction 1.2% 10.7%

Conclusion In conclusion, this investigation demonstrated that lead impurities can have a significant impact on the competence of single electron transfer processes that employ zero-valent zinc as the terminal reductant in methanolic aqueous solutions. The findings suggest that lead contamination of the Zn dust resulted in an enrichment of lead on the surface of the Zn dust, severe agglomeration, and ultimately a stalled reaction. It is possible that this finding has relevance beyond the zinc/lead mixture described herein, and given the prevalence of zero-valent metal



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reductions in the manufacture of commodity and fine chemicals, this study is expected to be relevant to practicing synthetic chemists worldwide.

Experimental Section General Procedure for the Selective Reduction of Dibromoimidazole. To a solution of 5.0 g (12.6 mmol) dibromoimidazole 57a in 20 ml of methanol and 5 ml of water was added 4.4 g (15.1 mmol, 1.2 eq.) of ethylenediaminetetraacetic acid, 4.8 ml ammonium hydroxide solution (~28%, 2.7 eq.) followed by 1.3 g zinc dust in one portion. The mixture was heated up to 40 oC and vigorously stirred for about 90 min or until the remaining 5 is less than 0.5 (area)% by HPLC12 normalized to the product 3. If necessary, additional small amount of zinc dust could be charged to complete the reaction. The mixture was then filtered on a Buchner funnel and the filtrate was mixed with 20 ml of brine and 35 ml of ethyl acetate. The organic layer separated and the washed with 20 ml brine followed by 30 ml of 0.5% citric acid aqueous solution to remove over reduced by-product 4. The solvent was then removed under vacuum on a rotovapor at 50 oC and residue dissolved in 20 ml of methanol at 50 oC. After cooling the solution to room temperature, 45 ml of water was added slowly over 3 hours. The resulting suspension was cooled to 15 oC and the product was collected by filtration on a Buchner funnel. The wet cake was dried in a vacuum oven at 60 oC to give 3.44 g (86%) white solids. All spectral data are consistent with those reported previously.7a

Specific Surface Area Measurement: Specific surface area measurements on samples are carried out by nitrogen adsorption using the BET adsorption model. The instrument used is a Micromeritics Gemini 2360 or equivalent nitrogen adsorption apparatus.


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X-Ray Photoelectron Spectroscopy Measurement: XPS data is quantified using relative sensitivity factors and a model that assumes a homogeneous layer. The analysis volume is the product of the analysis area (spot size or aperture size) and the depth of information. Photoelectrons are generated within the X-ray penetration depth (typically many microns), but only the photoelectrons within the top three photoelectron escape depths are detected. Escape depths are on the order of 15-35 Å, which leads to an analysis depth of ~50-100 Å. Typically, 95% of the signal originates from within this depth.

Acknowledgment We acknowledge Jason Ash for conducting SSA analysis and collecting SEM images, and Aldo Rancier for elemental analysis. We thank Benjamin D. Sherry, Narayan Variankaval, and Debra Wallace for helpful discussion.

References 1. (a) Negishi, E. Organometallics in Organic Synthesis; Wiley: New York, 1980. (b) Knochel, P.; Singer, R.D. Chem. Rev. 1993, 93, 2117. 2. Hudlicky, M. Reductions in Organic Synthesis; Wiley: New York, 1984. 3. Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem., 1994, 59, 2668. 4. Hensen, M. M.; Grutsch, Jr. J. Organic Process Research & Development, 1997, 1, 168. 5. Takai, K.; Kakiuchi, T.; Utimoto, K. J. org. Chem. 1994, 59, 2671



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6. Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi, C. M.; Graham, D. J.; Hu, B.; Huang, Q.; Kargman, S.; Kozlowski, J.; Liu, R.; McCauley, J. A.; Nomeir, A. A.; Soll, R. M.; Vacca, J. P.; Wang, D.; Wu, H.; Zhong, B.; Olsen, D. B.; Ludmerer, S. W. Chem. Med. Chem., 2013, 8, 1930. 7. (a) Mangion, I. K.; Chen, C.-y.; Li, H.; Maligres, P.; Chen, Y.; Christensen, M.; Cohen, R.; Jeon, I.; Klapars, A.; Krska, S.; Nguyen, H.; Reamer, R. A.; Sherry, B. D.; Zavialov, I., Org. Lett., 2014, 16, 2310. (b) Li, H.; Chen, C.-y.; Nguyen, H.; Cohen, R.; Maligres, P. E.; Yasuda, N.; Mangion, I.; Zavialov, I.; Reibarkh, M.; Chung, J. Y. L., J. Org. Chem., 2014, 79, 8533. (c) Li, H.; Belyk, K. M.; Yin, J.; Chen, Q.; Hyde, A.; Ji, Y.; Oliver, S.; Tudge, M. T.; Campeau, L.C.; Campos, K. R., J. Am. Chem. Soc., 2015, 137, 13728. 8. Zinc dust /powder were purchased from following suppliers: entry 1 (Zinc A) through entry 4 from Aldrich, entry 1, 98%,

Impact of Lead Impurities in Zinc Dust on the Selective Reduction of a

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