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Improved Preparation of a Key Hydroxylamine Intermediate for Relebactam: Rate Enhancement of Benzyl Ether Hydrogenolysis with DABCO Jianguo Yin, Mark Weisel, Yining Ji, Zhijian Liu, Jinchu Liu, Debra J. Wallace, Feng Xu, Benjamin D Sherry, and Nobuyoshi Yasuda Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00381 • Publication Date (Web): 01 Feb 2018 Downloaded from http://pubs.acs.org on February 1, 2018

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Organic Process Research & Development

Improved Preparation of a Key Hydroxylamine Intermediate for Relebactam: Rate Enhancement of Benzyl Ether Hydrogenolysis with DABCO Jianguo Yin, Mark Weisel, Yining Ji, Zhijian Liu, Jinchu Liu, Debra J. Wallace, Feng Xu, Benjamin D. Sherry and Nobuyoshi Yasuda* Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States

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ABSTRACT: Previous methods to prepare a bicyclic N-hydroxyl urea intermediate in the synthesis of the potent beta-lactamase inhibitor relebactam were effective, but deemed unsuitable for long-term use. Therefore, we developed an in-situ protection protocol during hydrogenolysis and a robust deprotection/isolation sequence of this unstable intermediate employing a reactive crystallization. During the hydrogenation studies, we discovered a significant rate enhancement of O-benzyl ether hydrogenolysis in the presence of organic amine bases, especially DABCO. The broader utility of the application of organic bases on the hydrogenolysis of a range of O- and N-benzyl-containing substrates was demonstrated.

KEYWORDS Relebactam, Hydrogenolysis, Organic base, Rate enhancement, Deprotection



Introduction Infectious disease caused by multi-drug resistant bacteria has become one of the most serious life threatening health problems. The increasing resistance of bacteria, especially Gram-negative species, is rooted in their secretion of beta-lactamases, which selectively hydrolyse beta-lactam antibiotics.1 Relebactam 1 (Scheme 1) is currently being evaluated in Phase III clinical trials as a potent beta-lactamase inhibitor to restore antibacterial activities of beta-lactam antibiotics.2 Large scale preparation of relebactam presented a multitude of synthetic challenges, many stemming from the highly strained diazabicyclooctanone framework. Formation and manipulation of the N-hydroxyl bicyclic urea 2 was particularly complex due to its reactivity, as exemplified in the process development of avibactam which shares a similar sub-structure.3 We previously reported two methods (Scheme 1) for the preparation of 2.4 The first4a described hydrogenolysis of N-Cbz protected compound 3 in the presence of Pd(OH)2/C and Boc2O in THF, affording 87% of crystalline 2 (Scheme 1a). The use of THF as a reaction solvent was critical to maintain 2 in solution during the hydrogenolysis reaction. The second4b approach did not require a protecting group switch, and afforded 90% yield of 2 (Scheme 1b); however, as we developed additional experience at pilot-scale with each of these processes certain liabilities began to surface. Specifically, the solubility of 2 in organic solvents is limited, and even in THF the solubility of 2 was only 31 mg/mL at room temperature. Since a reaction at elevated temperature was not desirable, separation from the heterogeneous catalyst required a relatively large volume of solvent, and consequently an extended time cycle for distillation at manufacturing scale. In addition, if the hydrogenolysis reaction were to stall, degradation of 2 was anticipated to be a significant competing process which could compromise yield and purity.


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Herein, we report a robust debenzylation process reliant on in-situ protection/deprotection sequence of the N-OH functional group in 2 which overcomes many of the challenges inherent in manipulating this sensitive compound. During the course of these studies we discovered a significant rate enhancement in the hydrogenolysis reaction when sub-stoichiometric amounts of tertiary amine bases were added, and found that this acceleration was observed with other benzyl ether substrates. Scheme 1. Preparation of the Key Hydroxylamine Intermediate 2 for Relebactam

Results and discussion At the outset of this work we had the benefit of earlier pilot-scale experience which highlighted the challenges associated with handling urea 2 in solution.3, 4a To this end, we sought to protect



the hydroxylamine in 2 during the de-benzylation reaction, only to reveal it at reaction completion in the context of a reactive crystallization. Protection was expected to stabilize 2, 5 and improve the solubility of the intermediate thereby minimizing reaction volume and improving cycle-time. A trimethylsilyl (TMS) group was identified as the optimal species due to the mild and rapid protection / deprotection sequence, and the expected higher solubility of the silyl protected intermediate in organic solvents. To our delight, in the presence of stoichiometric N,Obis(trimethylsilyl)acetamide (BSA),6 the TMS protected hydroxyl urea 5 was cleanly formed in nearly quantitative yield by hydrogenolysis of 4 with solid supported Pd catalysts such as Pd/C or Pd/Al2O3. Examining the behavior (with/without catalysts) of 5 indicated improved stability (relative to 2), and the efficient removal of the TMS group upon treatment with water in the presence of acid allowed for an efficient direct isolation of the desired crystalline hydroxyl urea 2. During development of this process significant rate differences in the hydrogenolysis reaction were observed, and ultimately traced back to different sources of BSA. After a careful examination we discovered certain lots of BSA were contaminated with up to 2 mol% of triethylamine (TEA), while other samples contained none of the amine impurity. Surprisingly, the hydrogenolysis reaction was significantly accelerated when TEA contaminated BSA was employed, a finding in contrast with reported examples of catalyst poisoning in O-benzyl ether hydrogenolysis reactions.7 In an effort to better understand this observation, a selection of basic additives were evaluated in the de-benzylation reaction under otherwise standard conditions without BSA (0.1 M substrate in THF, 5 wt% dry Pd/C, 50 psi hydrogen, room temperature). The additive amount employed was 2 mol% for 2,2'-dipyridyl and DABCO and 4 mol% for the


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other bases examined. All reactions were halted after 4 h, and the conversion was determined by quantitative HPLC analysis (Table 1). Table 1. Impact of Basic Additives on Benzyl Ether Hydrogenolysis

Entry 1 2 3 4 5 6 7 8

Additive None pyridine 2,6-lutidine 2,6-di-tert-butylpyridine 2,2’-dipyridyl lithium tert-amoxide TEA DABCO

pKa (DMSO) N/A 3.4 6.6 0.81 4.3 17 9.0 8.9

mol% 4 4 4 2 4

Conversion (%) 4 1 9 1 0 15

4 2

40 64

In the absence of any additive the reaction proceeded to only 4% conversion (entry 1). Pyridine (entry 2), 2,6-di-tert-butylpyridine (entry 4) and 2,2'-dipyridyl (entry 5) all resulted in lower conversion than the control reaction, with the latter completely suppressing hydrogenolysis. Employing 2,6-lutidine (entry 3) or lithium tert-amoxide (entry 6) afforded greater conversion than in the reaction without base, and pointed toward the subtle impact of this additive on conversion. Our early finding on the impact of TEA was confirmed (entry 7), but most interestingly the use of DABCO resulted in 64% conversion after only 4 h, a 16 fold increase in conversion over the control reaction (entry 8). After identifying DABCO as the most efficient additive amongst this set, a loading study was performed under the standard hydrogenolysis conditions (0.1 M THF solution of 4, 50 psi of H2,



1.8 mol% dry Pd/C (5 wt%), 1.25 equiv BSA, room temperature). Hydrogen uptake was monitored over 3 h8 at four different DABCO loadings (Figure 1).

Figure 1. Comparison of Hydrogen Uptakes at Different DABCO Loadings

All four reactions proceeded without an induction period, and the reaction in the absence of DABCO reached 28% conversion in 3 h, this difference relative to the data presented in Table 1 is attributed to the presence of BSA (see below). At a charge of only 0.5 mol% DABCO a significant rate acceleration was observed, with hydrogen uptake essentially plateauing after one


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hour and a quantitative yield determined by HPLC after 3 h. Only minor differences in rate and conversion were observed from 0.5 to 3 mol% DABCO (Figure 1). Therefore 1-2 mol% of DABCO was chosen to maximize the rate enhancement in the de-benzylation, establishing an approximately one to one mole ratio of DABCO to Pd. After establishing the optimal DABCO charge, other solid supported Pd catalysts were evaluated to determine if the rate acceleration was unique to the solid support. The reactions were conducted using a 0.2 M THF solution of 4 with 1.25 equiv of BSA with and without 2 mol% DABCO (Table 2). Table 2. Screening of Solid Support Pd Catalysts Catalyst Loading DABCO 5 wt% Pd/C 3 wt% 2 mol% 5 wt% Pd/C 3 wt% none 5 wt% Pd/Al2O3 5 wt% 2 mol% 5 wt% Pd/Al2O3 5 wt% none 5 wt% Pd/CaCO3 5 wt% 2 mol% 5 wt% Pd/CaCO3 5 wt% none 5 wt% Pd/BaSO4 5 wt% 2 mol% 5 wt% Pd/BaSO4 5 wt% none 20 wt% Pd(OH)2/C 1 wt% 2 mol% 20 wt% Pd(OH)2/C 1 wt% none

Time (h) 2 2 2 2 16 16 16 16 8 8

Yield (%) 100 8 100 9 38 2 58 9 52 45

In all cases, a significant increase in yield was observed when 2 mol% DABCO was present, even though the difference with Pd(OH)2/C was less than with other solid supported catalysts. This study established that either Pd/C or Pd/Al2O3 were equally efficient catalysts for the desired hydrogenolysis reaction. To differentiate the effects of DABCO and BSA, four reactions were conducted with 0.2 M THF solution of 4, 1.2 mol% Pd/Al2O3 (5 wt%), with/without 1.25 equiv of BSA and with/without 2 mol% DABCO under 50 psi of hydrogen at room temperature (Figure 2).



Figure 2. Comparison of Hydrogen Uptake Rates for the Reactions with/without DABCO and with/without BSA

As depicted in Figure 2, addition of DABCO with or without BSA significantly accelerated the hydrogenolysis reaction, though interestingly, the fastest rate was observed when both DABCO and BSA were present (green line, Figure 2). The data suggest that the free hydroxylamine 2, which is generated without BSA, may act as a weak catalyst poison in the reaction.3 To test this hypothesis, reactions were performed with 0.2 M THF solution of 4, 1.8 mol% Pd/Al2O3 (5 wt%) without DABCO and at four different BSA charges (0, 0.6, 1.2 and 2.0 equiv) under 50 psi of hydrogen at room temperature (Figure 3).


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Figure 3. Comparison of Hydrogen Uptake for Reactions with Different BSA Equivalents

Since DABCO was not added for this study, all the reactions proceeded slowly relative to the optimized conditions. However, the data clearly indicated that without BSA (green line) the reaction is slowest and stalls after 2 hours. The hydrogen uptake with 0.6 equiv of BSA (red line) began to plateau at 60% conversion (5 h). Since BSA can transfer one of two TMS groups to the free hydroxylamine 2 under such mild conditions (room temperature),6b the data suggest hydrogenolysis begins to stall once all the BSA was consumed to generate Ntrimethylsilylacetamide. Similar profiles were observed when 1.2 or 2.0 equiv of BSA were employed. The data support that free hydroxylamine intermediate 2 can act as a weak catalyst



poison,3 and that the role of BSA is to ensure rapid conversion of 2 to TMS protected 5 in situ. On the other hand, the role of DABCO is not clear at the present time, we speculate that DABCO may modify the surface of the solid support, or the Pd distribution between the solid phase and liquid phase, however no meaningful physical data could be obtained to support these hypotheses. Further studies are underway to better understand the role of DABCO.9 Our ultimate goal was to develop the most efficient and reliable process to manufacture Nhydroxyl urea 2. It is ideal if the process can use a single solvent, as a time consuming solventswitch could be avoided. A suitable reaction solvent must have a good solubility for the TMS protected 5 to ensure easy separation of the product from the solid catalyst. On the other hand, the solubility of 2 in the same solvent should be low enough to enable rapid product precipitation from the solution upon deprotection of 5. We identified isopropyl acetate (IPAc) as an ideal candidate, since the solubility of 2 in IPAc is low (2.1 mg/mL) and hydrogenolysis in IPAc under optimized conditions proceeded with a similar rate and impurity profile to the reaction in THF. Employing 5 wt% Pd/C rather than the alumina supported catalyst was preferred to simplify the recovery of Pd. In the presence of DABCO a catalyst loading of only 0.72 mol% (3 wt%) Pd/C was required to reach complete conversion in a few hours, where in the absence of DABCO more than 12 h were required for reaction completion even with 2.4 mol% of Pd/C (5wt%). After the hydrogenation was complete, the product solution was separated from the catalyst by filtration. Upon treatment of the filtrate with 2.6 equiv of water and a catalytic amount of acetic acid at room temperature hydroxyl urea 2 crystallized from the IPAc solution in a high purity and was obtained 88% isolated yield.10 This process was successfully implemented on pilot plant scale, as shown in Scheme 2. Scheme 2. Through Process for Preparation of 2


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The impact of DABCO on the reactivity of Pd/C, and other solid supported Pd catalysts, observed in the relebactam process could have broader implications. Therefore the generality of this rate acceleration was examined with a series of benzyl ether containing substrates (Table 3). Table 3. Generality of DABCO-Mediated Rate Acceleration in Benzyl Ether Hydrogenolysis Entry

Substrate

Product

Catalyst

Condition

Yield (%)

12%

A

100

18%

B

12

10%

A

96

10%

B

20

3%

A

79

3%

B

16

10%

A

39

10%

B

9

10%

C

98

6%

A

96

6%

B

17

6%

C

97

1

2

3

4

5



6

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20%

A

90

20%

B

49

20%

C

95

25%

A

6

25%

B

1

7

Reaction conditions; A: DABCO (3 mol%), 0.1 M THF, 5 wt% Pd/C, H2 (50 psi), rt, 4 h; B: 0.1 M THF, 5 wt% Pd/C, H2 (50 psi), rt, 4 h; C: DABCO (3 mol%), BSA (2.25 equiv), 0.1 M THF, 5 wt% Pd/C, H2 (50 psi), rt, 4 h. The hydrogenolysis reactions were carried out in the presence of 3 mol% DABCO (condition A) or 0 mol% DABCO (condition B) in 0.1 M THF solution in a glass Parr shaker with Pd/C (5 wt%) under 50 psi hydrogen pressure at room temperature. The reactions were halted after 4 h and the yields for the corresponding products were determined by HPLC. Phenolic benzyl ethers (entries 1, 2, and 6) and a benzyl ester (entry 3) all showed an increase in conversion in the presence of DABCO. Similarly, an N-Cbz group (entries 4 and 5) was removed more efficiently in the presence of DABCO. In the case of entry 4, the yield was dramatically improved by addition of BSA (condition C), which might be due to solubility of the product. The debenzylation of an N-benzyl imidazole containing substrate (entry 7) demonstrated a limitation of the current method, showing low conversion with or without DABCO present. Conclusion: A single solvent (IPAc) process for the formation of 2 was developed which relies on in-situ TMS ether formation during hydrogenolysis, and reactive crystallization of 2 by acidic


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deprotection after catalyst removal. A significant rate enhancement of the hydrogenolysis reaction through the addition of organic bases, specifically DABCO, was observed and found to be general for related de-benzylation reactions. These findings have allowed for the development of a robust scalable process to secure key bicyclic intermediate 2 in the synthesis of the betalactamase inhibitor relebactam. Experimental Section: All catalysts, reagents and solvents were obtained from commercial supplies and used without further purification prior to use unless otherwise stated. 5 wt% Pd/C was purchased from BASF Co. BSA was purchased from Gelest, Inc. (Contamination of TEA was less than 40 ppm by GC). DABCO and anhydrous THF were purchased from Sigma-Aldrich. General Procedure for the preparation of hydroxylurea 2 from 4 To a 2 L three necked round bottom flask containing 5wt% Pd/C (6.0 g, 50% water) was added IPAc (800 mL). The mixture was distilled at one atmosphere and about 200 mL was collected until the moisture content (determined by KF titration) of the remaining mixture was below 500 ppm. The mixture was cooled to room temperature and additional IPAc (400 mL) was added, followed by compound 4 (100.0 g, 0.218 mol), BSA (68.0 mL, 95 wt%, 0.264 mol) and DABCO (0.48 g, 4.28 mmol). The mixture was then hydrogenated in an autoclave at 50 psi and room temperature for 3 to 5 h until the remaining starting material was less than 0.5% as assessed by HPLC analysis. The mixture was filtered through one inch of Celite® in a Buchner funnel under nitrogen and the cake was rinsed with IPAc (500 mL). The solution was then concentrated at reduced pressure until the volume of the filtrate was 1.4 L. Analysis of the solution by HPLC indicated the solution contained 96.1g (100%) of 5.



A portion (400 mL) of the above filtrate containing 5 was charged into a 2 L three necked flask fitted with an overhead stirrer. After the solution was cooled to 15 oC, 28% aqueous acetic acid (5.5 g) was added in one portion. The mixture was then agitated at 15 oC for 1 h while adding one third of the remaining filtrate (333 mL) slowly. Product 2 was precipitated during the addition. To the resulting suspension was added additional 28% aqueous acetic acid (4.17 g) in one portion. The mixture was agitated for another 1 h at 15 oC while another one third of the filtrate (333 mL) was added slowly. After adding additional aqueous acetic acid (4.17 g), the rest of the filtrate (333 mL) was added over 1 h. The resulting suspension was agitated at 20 oC for 1 h followed by addition of methyl tert-butyl ether (600 mL). The mixture was then cooled to 5 oC over 1 h and the product 2 was collected by filtration. The cake was washed with dry IPAc (200 mL) and dried in a vacuum oven at 50 oC, to give 2 (70.7 g, 88%; residual Pd less than 5 ppm) as a colorless crystalline solid. The spectroscopic data is consistent with those reported previously.4 Alternatively, analytically pure crystalline 5 could be isolated by concentrating the filtrate and storing the solution at 5 oC overnight. 1H NMR (500 MHz, CDCl3): δ 6.58 (d, J=7.9 Hz, 1H), 4.10-3.86 (m, 4H), 3.55 (bs, 1H), 3.14 (bd, J=11.5 Hz, 1H), 2.86 (bt, J=12.0 Hz, 2H), 2.76 (d, J=11.5 Hz, 1H), 2.36 (dd, J=15.1, 7.1 Hz, 1H), 2.12 (m, 1H), 2.00-1.82 (m, 3H), 1.66 (m, 1H), 1.44 (s, 9H), 1.31 (m, 2H), 0.25 (S, 9H).

13

C NMR (125 MHz, CDCl3): δ 169.2, 168.3, 154.8,

79.8, 60.7, 60.0, 47.3, 46.9, 42.6 (br, 2C), 32.2, 31.9, 28.5 (3C), 20.5, 17.5, -0.75 (3C). (+)-ESI HRMS: C20H36N4NaO3Si, (M+Na)+ 463.2347; Found, 463.2348. Supporting Information The supporting Information is available free of charge on the ACS Publications website at DOI: 1

H and 13C NMR spectra of compound 5.


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Notes The authors declare no competing financial interest. Acknowledgement The authors acknowledge helpful discussions with Dr. Kevin R. Campos, Dr. Louis-Charles Campeau, Dr. Paul G. Bulger and Dr. Michael Kress.

Reference 1. a) Karam, G.; Chastre, J.; Wilcox, M. H.; Vincent,J.-L., Critical Care, 2016, 20:136; b) Zowawi, H. M.; Harris, P. N. A.; Roberts, M. J.; Tambyah, P. A.; Schembri, M. A.; Pezzani, M. D.; Willamson, D. A.; Paterson, D. L., Nature Reviews Urology, 2015, 12,570. 2. a) Haidar, G.; Clancy, C. J.; Chen, L.; Samanta, P.; Shields, R. K.; Kreiswirth, B. N.; Nguyen, M. H., Antimicrobial Agents and Chemotherapy, 2017, 61, e00642; b) Lob, S. H.; Hackel, M. A.; Kazmierczak, K. M.; Young, K.; Motyl, M. R.; Karlowsky, J. A.; Sahma, D. F., Antimicrobial Agents and Chemotherapy, 2017, 61, e02209. 3. During preparation of the penultimate tetrabutylammonium salt of avibactam, an in situ Osulfonylation was developed during the de-benzylation. The hydrogenolysis rate was carefully controlled to avid build up the unstable N-hydroxyl intermediate. See: a) Ball, M.; Boyd, A.; Ensor, G. J.; Evans, M.; Golden, M.; Linke, S. R.; Milne, D.; Murphy, R.; Telford, A.; Kalyan, Y.; Lawton, G. R.; Racha, S.; Ronsheim, M.; Zhou, S. H., Org. Process Res. Dev., 2016, 20, 1799; b) Wang, T.; Du, L.-d.; Wan, D.-j.; Chen, X.; Wu, G., Org. Process Res. Dev., just accepted.



4. a) Mangion, I. K.; Ruck, R. T.; Rivera, N.; Huffman, M. A.; Shevlin, M., Org. Lett., 2011, 13, 5480; b) Miller, S. P.; Zhong, Y. L.; Liu, Z.; Simeone, M.; Yasuda, N.; Limanto, J. Chen, Z.; Lynch, J.; Capodanno, V., Org. Lett., 2014, 16, 174. 5. The corresponding O-benzyl compounds are not reported as unstable in references 3 and 4. 6. a) Klebe, J. F.; Finkbeiner, H.; White, D. M., J. Am. Chem. Soc., 1966, 84, 3390.; b) El Gihani, M. T.; Heaney, H., Synthesis, 1998, 357. 7. a) Sajiki, H.; Hirota, K., Tetrahedron, 1998, 54, 13981.; b) Sajiki, H.; Hattori, K.; Hirota, K., J. Org. Chem., 1998, 63, 7990.; c) Sajiki, H.; Kuno, H.; Hirota, K., Tetrahedron Lett., 1998, 39, 7127.; d) Researchers at Abbott Laboratories reported rate enhancement in the hydrogenolysis of a benzyl ester in conjunction with the reduction of Ar-NO2 to aniline by addition of TEA. See: Seif, L. S.; Hannick, S. M.; Plata, D. J.; Morton, H. E.; Sharma, P. N., Chemical Industries (Dekker), 2003, 89, 633. 8. The progress of the reaction was also monitored with HPLC analysis and this data was in good correlation with the hydrogen uptake data. 9. Pd concentrations in solution during the hydrogenation with/without DABCO were similar and the highest concentration observed was about 1.8 ppm in both cases. Based on the preliminary studies of this hydrogenolysis, the reaction kinetics were zero-order with respect to the benzyl ether substrate. 10. Water activity was carefully controlled during reactive crystallization to avoid forming a less stable crystalline dihydrate.


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Rate Enhancement of Benzyl Ether ... - ACS Publications

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