A New Synthetic Route to Avibactam: Lipase ... - ACS Publications

Dec 7, 2017 - Frère, J. M.; Miossec, C.; Coleman, K.; Black, M. T. Antimicrob. Agents. Chemother. 2010, 54 (12), 5132−5138. (7) NXL104 Inhibition o...
1 downloads 0 Views 1MB Size
Download PDF
This article was retracted on May 3, 2018 (Org. Process Res. Dev. 2018, 22, DOI: 101021/acs.oprd.8b00137) Article Cite This: Org. Process Res. Dev. 2018, 22, 267−272

pubs.acs.org/OPRD

A New Synthetic Route to Avibactam: Lipase Catalytic Resolution and the Simultaneous Debenzylation/Sulfation Tao Wang,†,§ Liang-Dong Du,‡ Ding-jian Wan,‡ Xiang Li,‡ Xin-Zhi Chen,*,§ and Guo-Feng Wu*,† †

Research & Development Center, Zhejiang Medicine Co., Ltd., 59 East Huangcheng Road, Xinchang, Zhejiang 312500, P. R. China Shanghai Laiyi Center for Biopharmaceuticals R&D, 5B, Building 8 200 Niudun Road, Pudong District, Shanghai, 201203, P. R. China § Key Laboratory of Biomass Chemical Engineering of Ministry of Education, Zhejiang University, 38 Zhejiang University Road, Xihu District, Hangzhou, 310007, P. R. China

Org. Process Res. Dev. 2018, 22, DOI: 10.1021/acs.oprd.8b00137 S Supporting Information *

ABSTRACT: An efficient synthesis of avibactam starting from commercially available ethyl-5-hydroxypicolinate was completed in 10 steps and 23.9% overall yield. The synthesis features a novel lipase-catalyzed resolution, in the preparation of (2S,5S)-5hydroxypiperidine-2-carboxylate acid, which is a valuable precusor of the key intermediate ethyl (2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxylate. An optimized one-pot debenzylation/sulfation reaction, followed by cation exchange, gave the avibactam sodium salt on a 400.0 g scale.

■

INTRODUCTION Avibactam (1, Figure 1), sodium (2S,5R)-2-carbamoyl-7-oxo1,6-diazabicyclo[3.2.1]octan-6-yl sulfonate, containing a

antibacterial activity, but its combination with antibiotics can be used to avoid bacterial resistance and enhance the effect.5,12,13 The concept of avibactam has its origins in research from Hoechst Marion Roussel, who proposed that DBO might act to acylate nucleophilic enzymes in a manner analogous to βlactams.14 It has been proven that avibactam has excellent antibacterial activity and plays an irreplaceable role in the treatment of infection with drug-resistant bacteria. Substantial effort has been devoted to the preparation of avibactam14−26 (Scheme 1). Initially, the Aventis infection division in Romainville (France) disclosed route A for its synthesis in the early stage of drug discovery.17,19 In this process, double-chiral piperidine derivatives were used as starting material to provide avibactam via inversion of configuration, deprotection, urea-cyclization, deprotection, and sulfonation with about 9.0% total yields. Miller et al. also prepared avibactam based on route A.23 This route suffers from a long synthetic procedure, low yield, and heavy laborious workups. Besides, the raw materials (double-chiral piperidine derivatives) are expensive and a number of environmentally undesirable reagents and solvents are required in this route. The Wockhardt developed route B to obtain avibactam from Lglutamate acid or L-pyroglutamic acid.18 In this route, the skeleton of the target molecular diazabicyclo[3.2.1]octane heterocyclic core structure (DBO) was constructed through the steps of ring-opening, ring-closing, deoxygenization, and then by deprotection, sulfonation, and other steps to obtain avibactam with a total yield of about 11.0%. This method, producing small scale avibactam in a single batch, has some drawbacks limiting the large-scale synthesis: (a) a long synthetic procedure, (b) complicated purification process, and

Figure 1. Structure of avibactam sodium (1).

diazabicyclo[3.2.1]octane (DBO) heterocyclic core structure, is a novel diazabicyclooctane non-β-lactama β-lactamase inhibitor.1−4 It has a unique mechanism of inhibition among β-lactamase inhibitors, which is able to bind reversibly and covalently to β-lactamase.2,5 As a new drug featured with bacterial resistance, avibactam has been widely used in clinic and its combination with Ceftazidime (Zavicefta) has recently been approved by the EMA and FDA for treatment of complicated intra-abdominal infectious (CIAI), complicated urinary tract infectious (CUTI), hospital acquired pneumonia (HAP), etc.6,7 Moreover, compared with the three known βlactamase inhibitors named clavulanic acid, sulbactam, and tazobactam, the efficiency of avibactam is stronger and its spectrum is also broader: avibactam is active against class A including Class A Klebsiella pneumoniae carbapenemase (KPCs) and ESBLs, class C, and some class D β-lactamases.8,9 In the past decades, antibiotics containing highly active βlactam ring systems, such as Penicillium, Cephalosporins, and others, have been widely used to treat bacterial infections worldwide. Resistance to the β-lactam antibacterials is an increasing serious problem, as is the case for all antibacterials.10,11 Avibactam alone has not useful regarding intrinsic

R

Downloaded via 80.82.77.83 on June 21, 2018 at 22:31:02 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

et ra ct ed

‡

© 2017 American Chemical Society

Received: September 5, 2017 Published: December 7, 2017 267

DOI: 10.1021/acs.oprd.7b00290 Org. Process Res. Dev. 2018, 22, 267−272

Organic Process Research & Development

Article

et ra ct ed

Scheme 1. Reported Synthetic Routes to Avibactam

Scheme 2. Our Route to Synthesize Avibactam

(c) the employment of excessive environmentally unfriendly reagents such as diphosgene. Recently, AstraZeneca and Forest Laboratories have optimized the process: from commercially available Boc-benzylglutamate in only 5 isolated steps with an overall yield of 35.0% (without including the construction of DBO).26 Another route is based on the olefin metathesis reaction to construct the DBO skeleton24 (Route C). However, the decomposition of olefins generally leads to lower yield, substrate instability, the need for chiral ligand participation, less stereoselectivity, and other issues. These methods mentioned above are usually restrictive, and difficult to implement in industrial production.

R

the ring-opening and carbonized cyclization reaction steps used in previous reported routes; (2) a novel lipase-catalyzed resolution was used to synthesize (2S,5S)-5-hydroxypiperidine-2-carboxylate acid, which is a valuable precursor of the key intermediate ethyl (2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxylate; (3) an optimized debenzylation− sulfation reaction was developed, and environmental friendly solvents and reagents were used. New Approach to 7 from 2. In our new route (route D), an efficient synthesis of intermediate 7 is crucial to the viability of the project. Starting from commercially available ethyl-5hydroxypicolinate (2) (Scheme 3), compound 3 was obtained with a stereoisomer ratio of 97:3 (cis/trans) through the catalytic hydrogenation reaction. Without further purification, the crude 3 underwent the lipase (Lipozyme CALB21)catalyzed resolution to successfully give compound 4 as a single enantiomer with d.r. ≥ 99:1, along with a small amount of the side-product 4′.15b Subsequently, a mixture of (Boc)2O

■

RESULT AND DISCUSSION Based on earlier reports,16−20 we optimized the process of preparing avibactam (Scheme 2). Three key changes are made: (1) the commercially available and affordable ethyl-5hydroxypicolinate was used as the starting material, avoiding 268

DOI: 10.1021/acs.oprd.7b00290 Org. Process Res. Dev. 2018, 22, 267−272

Organic Process Research & Development

Article

et ra ct ed

Scheme 3. Synthetic Route to the Key Intermediate (7)

for each step. So an alternative strategy was used by reversing the sequence of reaction steps, that is, amide formation first followed by the formation of the urea subunit. Fortunately, when compound 7 was subjected to a solution of NH3/ MeOH/toluene, the amide 9 was obtained in 96.5% yield. Much effort was devoted toward introducing the fragile urea bond in compound 10 (Scheme 4). Initially, we tried the direct urea-unit formation using triphosgene, but it proved to be unsuccessful. Use of alternative phosgenating agents (such as CDI and various chloroformates) also failed, but these experiments clearly revealed that the two nitrogens in the molecule can be selectivily reacted, which is consistent with the report by Matthew Ball et al. 26 Inspired by earlier reports,16,18−20,23,25,26 we predict that the introduction of the Boc or FMOC protecting groups on the nitrogen might favor the formation of 10 directly from 9. Due to the much milder deprotection conditions required to remove the FMOC group, the FMOC approach was selected for further studies. Solvent had a significant effect on the outcome of the reaction. Many solvents were screened, and chlorobenzene was found to be suitable and facilitate the operable processing. Under the optimized reaction conditions, compound 10 with high quality was successfully prepared in 89% yield. The total yield for the preparation of 10 starting from compound 7 is up to 90%. Synthesis of 13 by One-Pot Deprotection and Sulfation. Significant progress has been made in optimizing the process to synthesize 13 from 10 (Scheme 5). Typically, the simultaneous catalytical deprotection of the Bn group with Pd/C as catalyst and sulfation gave the intermediate 12. Without further purification, compound 12 was subjected to a cation exchange reaction to give compound 13. It is worth noting that the debenzylative intermediate 11 was nucleophilic enough to react with the commercially available sulfur trioxidetrimethylamine (SO3·NMe3) to form compound 12. Another advantage of the transformation is that a more environmentally friendly water/isopropyl alcohol (1:1) system was used to replace other organic solvents. Thus, an efficient synthesis of avibactam was completed in 10 steps and 23.9% overall yield.

and TEA was added dropwise to the aqueous solution of 4 and 4′, and the mixture was stirred at room temperature for 18 h to give (2S,5S)-1-tert-butyl-2-ethyl-5-hydroxy-piperidine-1,2-dicarboxylate (5) and byproduct 5′.15b Compound 5′ is watersoluble and was removed by liquid separation so that pure product 5 was easily obtained. Chemical catalytic methods to prepare 5 directly from compound 3 were also tried, but the stereoselectivity is relatively poor (d.r. ≈ 1:1). Overall, compound 5 was obtained using relatively environmental friendly methods, and the total yield for the above three steps is up to 42.9%. Next, compound 5 was dissolved in CH3CN and stirred at −30 °C for 30 min. 2,6-Dimethylpyridine and trifluoromethanesulfonic anhydride were successively added to the reaction solution followed by the addition of a solution of NH2OBn in 2,6-dimethylpyridine. The mixture was stirred at room temperature for 12 h to give compound 6. The key intermediate 7 was afforded by removing the protecting group Boc using TFA. The total yield for the last two steps is 75.2%. New Approach To Obtain 10 from 7. An efficient synthesis of pure compound 7 offered new approaches to the synthesis of 10, avoiding the selective hydrolysis of the trans benzyl ester of 8 (Scheme 4). First, we tried a synthetic route including the urea-unit formation (7 to 8) and the ester to amide conversion (8 to 10). However, the yield was always low

R

Scheme 4. Conversion 7 to Urea 10

269

DOI: 10.1021/acs.oprd.7b00290 Org. Process Res. Dev. 2018, 22, 267−272

Organic Process Research & Development

Article

et ra ct ed

Scheme 5. Synthetic Routes to Intermediate 13 and 1

■

CONCLUSION In summary, we have developed an alternative scalable process for the synthesis of avibactam (1) from commercially available and affordable ethyl 5-hydroxypicolinate (2), validated on a 400.0 g scale. The lipase-catalyzed resolution (Lipozyme CALB) was used to construct the two chiral carbon centers, and excellent stereoselectivity was achieved. The efficiency and operability of the formation of the urea-unit of avibactam (1) was greatly improved by introduction of a protecting group strategy. Moreover, the simultaneous debenzylation−sulfation in a one pot has reduced cost and improved efficiency. Lastly, we chose environmental friendly solvents and reagents and increased the process efficiency by reducing extractions and improving ease of purification operation.

at room temperature for 12 h until completion of the reaction (by TLC analysis). The aqueous solution of 4 (8.53 L) was obtained by filtration and directly used for the next step. Preparation of (2S,5S)-1-tert-Butyl-2-ethyl-5-hydroxypiperidine-1,2-dicarboxylate (5). Triethylamine (407 mL, 2.92 mol) was added to a mixture of the aqueous solution of 4 (8.53 L) and THF (8 L) at room temperature. Then (Boc)2O (101.0 g, 1.752 mol) was added dropwise to the mixture at 0 °C. The reaction mixture was stirred at room temperature for 18 h until completion of the reaction (by TLC analysis). Then, the reaction mixture was extracted three times with ethyl acetate (3 L × 3). The byproduct 5′ is water-soluble and remained in the aqueous solution. The combined organic layers were dried over anhydrous MgSO4. Evaporation of the solvent under vacuum, followed by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4/1), gave the corresponding product 5, as a pale yellow liquid (175.8 g, the three step total yields 42.9%), [α]20 D = −101.59 (c = 0.62, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.73 (d, J = 87.9 Hz, 1H), 4.21 (s, 2H), 4.10 (d, J = 9.0 Hz, 1H), 3.64 (s, 1H), 2.72 (dt, J = 50.3, 11.5 Hz, 1H), 2.29 (s, 1H), 1.98 (d, J = 10.3 Hz, 1H), 1.81−1.67 (m, 1H), 1.64 (s, 1H), 1.60 (s, 1H), 1.46 (d, J = 17.5 Hz, 9H), 1.28 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.47 (s), 155.55 (s), 80.55 (s), 66.57 (d, J = 22.1 Hz), 61.27 (s), 53.35 (d, J = 119.3 Hz), 48.00 (d, J = 84.9 Hz), 30.12 (d, J = 58.6 Hz), 28.29 (s), 24.91 (d, J = 22.5 Hz), 14.22 (s). IR (cm−1): 2979, 1741, 1699, 1403, 1370, 1149, 1073, 1024. MS (ESI) m/z: 296.1 [M + Na]+ Preparation of (2S,5R)-1-tert-Butyl-2-ethyl 5-((Benzyloxy)amino)piperidine-1,2-dicarboxylate (6). 2,6-Dimethylpyridine (95.0 mL, 805.0 mmol) and Tf2O (131 mL, 778 mmol) were added successively, dropwise, to a mixture of 5 (202.0 g, 741.0 mmol) in CH3CN (2000 mL) at −30 °C, and the reaction mixture was stirred at this temperature for 15 min. NH2OBn and 2,6-dimethylpyridine (95 mL, 805.0 mmol) were slowly added to the reaction solution at −30 °C. Then, the reaction mixture was stirred at 0 °C for 30 min and at room temperature for 12 h. The reaction mixture was extracted with ethyl acetate (600 mL × 3), and the combined organic layers were dried over anhydrous MgSO4. Evaporation of the solvent under vacuum gave the corresponding crude product 6 (280.2 g). The crude product 6 was directly used for the next step without further purification. The pure product 6 is a white solid, mp 122.3− 1 125.2 °C; [α]20 D = −81.59 (c = 0.63, CHCl3); H NMR (500

■

R

EXPERIMENTAL SECTION General. Unless otherwise mentioned, all commercial reagents and solvents were used directly as purchased. Flash chromatography was performed on silica gel with petroleum ether/ethyl acetate or dichloromethane/methanol as the eluent. Melting points were uncorrected. Optical rotations were measured with a sodium lamp. NMR spectra were recorded on a spectrometer at 500 MHz (1H NMR), 101 or 126 MHz (13C NMR). The mass data were recorded on a high-resolution mass spectrometer in the ESI mode. Chemical shifts (δ) are reported in parts per million and referenced to the residual solvent peak, and J values are given in hertz (Hz). Preparation of Ethyl 5-Hydroxypiperidine-2-carboxylate (3). Rh/C (25.0 g, 10%) was added to a mixture of ethyl5-hydroxypicolinate (2) (250.0 g, 1.496 mol) and ethanol (1500.0 mL) in a vessel. The reaction mixture was stirred under the atmosphere of hydrogen (200.0 psi) at room temperature for 12 h until completion of the reaction (by TLC analysis). Then, the mixture was filtered and the solvent was removed under reduced pressure to obtain the crude ethyl 5hydroxypiperidine-2-carboxylate (3) (253.0 g). The crude 3 was directly used in the next step without further purification. Preparation of Ethyl (2S,5S)-5-Hydroxypiperidine-2-carboxylate (4). The crude 3 (253.0 g, 1.460 mol) was dissolved in a potassium phosphate buffer solution (8.53 L, 0.1 M, pH = 8). The pH of the solution was adjusted to 7.5 with dipotassium hydrogen phosphate followed by the addition of Lipozyme CALB (253.0 g, 5000 LU/g) . The reaction mixture was stirred

270

DOI: 10.1021/acs.oprd.7b00290 Org. Process Res. Dev. 2018, 22, 267−272

Organic Process Research & Development

Article

MHz, CDCl3) δ 7.39−7.32 (m, 4H), 7.32−7.27 (m, 1H), 5.47 (s, 1H), 4.72 (dd, J = 25.9, 11.5 Hz, 3H), 4.19 (dd, J = 14.0, 7.0 Hz, 3H), 3.14 (t, J = 36.2 Hz, 2H), 1.96 (s, 2H), 1.69 (d, J = 13.9 Hz, 1H), 1.46 (s, 10H), 1.29−1.24 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 137.92 (s), 128.53 (s), 128.37 (s), 127.80 (s), 80.19 (s), 76.66 (s), 61.07 (s), 53.68 (s), 53.26 (s), 42.76 (s), 28.37 (s), 22.98 (s), 21.26 (s), 14.28 (s). IR (cm−1): 3242, 2947, 1738, 1674, 1427, 1152, 1195, 1030, 701. MS (ESI) m/z: 379.2 [M + H]+ Preperation of Ethyl (2S,5R)-5-((Benzyloxy)amino)piperidine-2-carboxylate (7). Trifluoroacetate acid (124.0 mL, 1.665 mol) was added dropwise to the solution of the crude product 6 (280.2 g) in CH2Cl2 (1500 mL) at 0 °C. The mixture was stirred at rt for 15 h. The pH of the reaction solution was adjusted to 10 with saturated sodium bicarbonate solution. Then, the reaction mixture was extracted with DCM (600 mL × 3), and the combined organic layers were dried over anhydrous MgSO4. Evaporation of the solvent under vacuum, followed by flash column chromatography on silica gel (DCM/ MeOH = 20/1)), gave the corresponding crude product 7, as a pale yellow liquid (155.4 g, the two step total yields 75.2%), 1 [α]20 D = −10.40 (c = 0.92, CHCl3); H NMR (500 MHz, CDCl3) δ 7.41−7.32 (m, 4H), 7.33−7.21 (m, 1H), 4.89−4.42 (m, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.38 (ddd, J = 11.9, 4.0, 1.8 Hz, 1H), 3.27 (dd, J = 11.0, 3.1 Hz, 1H), 2.99 (tt, J = 10.5, 4.0 Hz, 1H), 2.44 (dd, J = 11.9, 9.8 Hz, 1H), 2.07 (ddd, J = 17.0, 8.5, 4.6 Hz, 1H), 2.01−1.89 (m, 1H), 1.53 (tdd, J = 13.0, 11.1, 3.8 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 173.07 (s), 137.78 (s), 128.37 (s), 127.84 (s), 76.78 (s), 60.84 (s), 58.41 (s), 57.10 (s), 49.44 (s), 28.10 (s), 28.01 (s), 14.20 (s). IR (cm−1): 3270, 2930, 1736, 1453, 1191, 1033, 746, 695. MS (ESI) m/z: 279.0 [M + H]+. Preperation of (2S,5R)-5-((Benzyloxy)amino)piperidine-2carboxamide (9). Ethyl (2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxylate 7 (593.0 g, 2.130 mol) was mixed with a solution of 7 M ammonia in methanol (2 L). The reaction mixture was stirred at rt for 8 h until completion of the reaction (by TLC analysis). The solid was removed by filtration, and the obtained cake was washed with methanol (2 × 0.5 L). The filtrates were combined and concentrated under vacuum to 1.50 L (cautiouly, warming from 0 °C) followed by the addition of toluene (3 L). This operation is repeated twice in succession. The obtained solution was stirred at 80 °C for 0.5 h. Then it was cooled to 0 °C. The crude product 9 precipitated and was obtained by filtration and washed with methyl tert-butyl ether (1000 mL × 3) and dried in vacuum to give the pure 9 as a white solid (510.1 g, 96.5%), 1 mp 148.2−150.9 °C; [α]20 D = −19.20. (c = 0.36, CHCl3); H NMR (400 MHz, DMSO) δ 7.58−7.17 (m, 5H), 7.10 (s, 1H), 6.92 (s, 1H), 6.48 (d, J = 6.0 Hz, 1H), 4.57 (s, 2H), 3.13 (dd, J = 11.9, 2.4 Hz, 1H), 2.87 (dd, J = 11.0, 2.7 Hz, 1H), 2.81−2.68 (m, 1H), 2.21 (dd, J = 11.8, 10.2 Hz, 1H), 1.88−1.76 (m, 2H), 1.34−1.20 (m, 1H), 1.11 (ddd, J = 17.5, 12.9, 4.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 176.31 (s), 137.69 (s), 128.45 (s), 128.43 (s), 127.94 (s), 76.90 (s), 59.74 (s), 57.01 (s), 49.25 (s), 28.17 (s), 27.76 (s). IR (cm−1): 3378, 2946, 1624, 1438, 1323, 1122, 824, 698. MS (ESI) m/z: 250.2 [M + H]+. Preperation of (2S,5R)-6-(Benzyloxy)-7-oxo-1,6diazabicyclo[3.2.1]octane-2-carboxamide (10). (2S,5R)-5[(Benzyloxy)amino]piperidine-2-carboxamide 9 (510.1 g, 2.045 mol) was mixed with di-isopropylethylamine (381 mL, 2.188 mol) and chlorobenzene (3.0 L) at 20 °C. The solution of 9-fluorenylmethyl chloroformate (540.2 g, 2.086 mol) in

R

et ra ct ed

chlorobenzene (3.1 L) was added to the reaction mixture. The mixture was stirred at 30 °C until completion of the reaction. Then carbonyl diimidazole (331.3 g, 2.658 mol, dropwisely) was added, and agitation was continued at 15 °C for 11 h until completion of the reation. Diethylamine (529 mL, 5.112 mol) was added, and agitation was continued at rt for 2 h. Aqueous 3 M hydrochloric acid (3.2 L, 9.600 mol) was added (to achieve a pH of 2 to 6), and the mixture was cooled to 0 °C. The solid was isolated by filtration, washed with water (1.50 L × 2.0) and 1-chlorobutane (1.50 L × 2.0), and dried to give the title compound as a white crystalline solid (495.0 g, 89%), mp 1 154.2−156.1 °C; [α]20 D = −23.57 (c = 0.65, CHCl3); H NMR (400 MHz, DMSO) δ 7.45 (dd, J = 7.8, 1.6 Hz, 2H), 7.43−7.33 (m, 4H), 7.30 (s, 1H), 4.93 (q, J = 11.3 Hz, 2H), 3.69 (d, J = 6.9 Hz, 1H), 3.62 (s, 1H), 2.90 (s, 2H), 2.22−1.94 (m, 1H), 1.93−1.76 (m, 1H), 1.75−1.50 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 172.27 (s), 167.70 (s), 135.60 (s), 129.24 (s), 128.84 (s), 128.59 (s), 78.30 (s), 59.18 (d, J = 253.0 Hz), 57.92 (s), 47.80 (s), 20.86 (s), 17.31 (s). IR (cm−1): 3406, 2991, 1761, 1663, 1455, 1386, 1022, 755. MS (ESI) m/z: 298.1 [M + Na]+. Preparation of Tetrabutylammonium [(2S,5R)-2-Carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl] Sulfate (13). (2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2carboxamide 10 (495.0 g, 1.792 mol) was mixed with a sulfur trioxide trimethylamine complex (301.0 g, 2.150 mol), triethylamine (65 mL, 890 mmol), 10% w/w Pd/C (40 g, 0.025 wt), isopropanol (2.50 L), and water (2.50 L). This mixture was then held in a hydrogenation vessel and flushed with nitrogen at ambient pressure. Hydrogen was then fed into the vessel at 0.4 mol equiv per hour until the debenzylation reaction was completed. The catalyst was removed by filtration and washed with water. The combined filtrates were washed with n-butyl acetate (2.0 L). A solution of tetrabutylammonium acetate (812.0 g, 2.698 mol) and acetic acid (11 g, 180 mmol) in water (1.00 L) was prepared. 72% of the tetrabutylammonium acetate solution was added to the reaction mixture, which was then extracted with DCM (2.00 L). The remaining 28% of the tetrabutylammonium acetate solution was added to the reaction mixture which was then extracted with DCM (1.50 L). The organic extracts were combined and concentrated to 1.50 L followed by the addition of 4-methyl-2-pentanone (1.25 L). The reaction mixture was cooled to 0 °C to precipitate the desired product 13. Compound 13 was collected by filtration, washed with 4-methyl-2-pentanone (1.00 L), and dried to yield a white crystalline solid 13 (814.0 g, 89.6%), mp 180.3−182.4 1 °C (decomposition); [α]20 D = −23.20 (c = 0.57, CHCl3); H NMR (500 MHz, DMSO) δ 7.36 (d, J = 78.9 Hz, 1H), 3.98 (s, 1H), 3.68 (d, J = 6.6 Hz, 1H), 3.33 (s, 1H), 3.27−3.12 (m, 4H), 3.01 (d, J = 11.6 Hz, 1H), 2.92 (d, J = 11.7 Hz, 1H), 2.14−1.97 (m, 1H), 1.84 (d, J = 6.0 Hz, 1H), 1.66−1.47 (m, 5H), 1.44−1.18 (m, 4H), 0.94 (t, J = 7.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 172.29 (s), 166.04 (s), 60.52 (s), 58.69 (s), 57.86 (s), 48.13 (s), 23.95 (s), 20.78 (s), 19.71 (s), 17.24 (s), 13.68 (s). IR (cm−1): 3474, 2964, 1761, 1694, 1488, 1272, 1007, 612. MS (ESI) m/z: 288.0 [M + Na]+. Preparation of Avibactam Sodium Salt (1). A solution of sodium 2-ethyl hexanoate (475.0 g, 2.850 mol) in ethanol (2.00 L) was added to a solution of tetrabutylammonium [(2S,5R)-2carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl] sulfate 13 (723.0 g) in ethanol (2.50 l) and water (50 mL) over approximately 1 h, and the temperature was maintained at rt. The reaction mixture was held for 2 h. The product was filtered, washed with ethanol (2 × 2.0 L), and dried to yield a white

271

DOI: 10.1021/acs.oprd.7b00290 Org. Process Res. Dev. 2018, 22, 267−272

Organic Process Research & Development

Article

crystalline solid 1 (395.0 g, 96.2%), mp 259.1−262.4 °C (decomposition); [α]20 D = −46.40 (c = 0.79, MeOH/H2O = 1/ 1); 1H NMR (500 MHz, D2O) δ 4.15 (dd, J = 5.8, 2.8 Hz, 1H), 4.01 (d, J = 7.5 Hz, 1H), 3.28 (d, J = 12.2 Hz, 1H), 3.06 (d, J = 12.2 Hz, 1H), 2.23−2.09 (m, 1H), 2.06−1.96 (m, 1H), 1.94− 1.82 (m, 1H), 1.81−1.69 (m, 1H). 13C NMR (126 MHz, D2O) δ 174.72 (s), 169.53 (s), 60.43 (s), 59.93 (s), 47.33 (s), 20.03 (s), 18.31 (s). IR (cm−1): 3459, 1749, 1675, 1361, 1270, 1013, 857, 768. MS (ESI) m/z: 279.0 [M + H]+.

■

Abilova, V.; Pyshnik, G.; Spasojevic, T. Lancet Infect. Dis. 2014, 14 (5), 381−387. (13) Chahine, E. B.; Sourial, M.; Ortiz, R. Consult Pharm 2015, 30 (12), 695−705. (14) Dubreuil, L. J.; Mahieux, S.; Neut, C.; Miossec, C.; Pace, J. Int. J. Antimicrob. Agents 2012, 39 (6), 500−504. (15) (a) Mangion, I. K.; Ruck, R. T.; Rivera, N.; Huffman, M. A.; Shevlin, M. Org. Lett. 2011, 13 (20), 5480−5483. (b) Krishnamurthy, S., Venkataprasad, J., Vagvala, T. C., Moriguchi, T., Tsuge, A. RSC Advances, 5(64), 52154−52160. (16) (a) Aventis Pharma SA: WO2002010172, 2002. (b) AstraZeneca: WO2012172368, 2012. (c) Merck: WO2009091856, 2009. (d) Merck: WO2012086241, 2012. (17) (a) Aszodi, J.; Lampilas, M.; Fromentin, C.; Rowlands, D. A. Aventis Pharma SA, FR, 2835186 (2003). (c) Novexel: WO2008142285, 2008. (18) (a) Patil, V. J.; Tadiparthi, R.; Birajdar, S.; Bhagwat, S. P. US8969334, 2015. (b) Hecker, E. A.; Baldwin, A. B-lactamase inhibitor picoline salt: P, US9120796, 2015. (c) Aszodi, J.; Fromentin, C.; Lampilas, M.; Rowlands, D. A. P. US7612087, 2009. (d) Gu, Y. G.; He, Y.; Yin, N.; Alexander, D. P. WO2013149136, 2013. (e) Hwang, Y. S.; Gu, J. Q.; Jain, A.; Garad, S.; Jacob, P. S. P. US20140275001, 2014. (f) Hecker, E. A.; Baldwin, A. P. US20159120796, 2015. (19) Baldwin, J. E.; Adlington, R. M.; Godfrey, C. R.; Gollins, D. W.; Smith, M. L.; Russel, A. T. Synlett 1993, 1993 (01), 51−53. (20) Abe, T.; Okue, M.; Sakamaki, Y. P. US8,772,490, 2014-7-8. (21) (a) Pietruszka, J.; Simon, R. C.; Kruska, F.; Braun, M. Eur. J. Org. Chem. 2009, 2009 (35), 6217−6224. (b) Anderson, B. A.; Hansen, M. M.; Harkness, A. R.; Henry, C. L.; Vicenzi, J. T.; Zmijewski, M. J. J. Am. Chem. Soc. 1995, 117 (49), 12358−12359. (c) Hirose, Y.; Kariya, K.; Sasaki, I.; Kurono, Y.; Ebiike, H.; Achiwa, K. Tetrahedron Lett. 1992, 33 (47), 7157−7160. (22) (a) Mangion, I. K.; Ruck, R. T.; Rivera, N.; Huffman, M. A.; Shevlin, M. Org. Lett. 2011, 13 (20), 5480−5483. (b) Chavan, V. P., Wankhede, K. S.; Deshmukh, V. V.; Bhavsar, S.; Patil, K. R.; Yeole, R. D.; Patel, M. V. US Patent Application 15,125,554, 2015-3-12. (23) Miller, S. P.; Zhong, Y. L.; Liu, Z.; Simeone, M.; Yasuda, N.; Limanto, J.; Chen, Z.; Lynch, J.; Capodanno, V. Org. Lett. 2014, 16 (1), 174−177. (24) Xiong, H.; Chen, B.; Durand-Réville, T. F.; Joubran, C.; Alelyunas, Y. W.; Wu, D.; Huynh, H. ACS Med. Chem. Lett. 2014, 5 (10), 1143−1147. (25) Priour, A.; Bonnet, A.; Oddon, G.; Mazurie, A. WO2009090320, 2009. (b) Lampilas, M.; Aszodi, J.; Rowlands, D. A.; Fromentin, C. WO2002010172, 2002. (c) Dedhiya, M. G.; Bhattacharya, S.; Ducandas, V.; Giuliani, A.; Ravaux, V.; Bonnet, A.; Priour, A.; Spargo, P. US8471025, 2013. (26) 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.; Zhou, S. H. Org. Process Res. Dev. 2016, 20 (10), 1799−1805.

ASSOCIATED CONTENT

S Supporting Information *

et ra ct ed

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.7b00290. Chiral HPLC report of compound 5; Copies of 1H and 13 C NMR spectra of compounds (PDF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail:[email protected] (G.-f.W.). *E-mail:[email protected] (X.-z.C.). ORCID

Guo-Feng Wu: 0000-0001-7072-1450 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors would like to thank the Research&Development Center, Zhejiang Medicine Co. and Zhejiang University. The research was supported in part by Zhejiang Province Human Resources and Social Security Department.

■

REFERENCES

R

(1) Bonnefoy, A.; Dupuis-Hamelin, C.; Steier, V.; Delachaume, C.; Seys, C.; Stachyra, T.; Fairley, M.; Guitton, M.; Lampilas, M. Journal of Antimicrobial Chemistry 2004, 54 (2), 410−417. (2) Aszodi, J.; Fromentin, C.; Lampilas, M.; Rowland, D. WO20033063864, 2003. (3) Ehmann, D. E.; Jahić, H.; Ross, P. L.; Gu, R. F.; Hu, J.; Kern, G.; Fisher, S. L. Proc. Natl. Acad. Sci. U. S. A. 2012, 109 (29), 11663− 11668. (4) Zhanel, G. G.; Lawson, C. D.; Adam, H.; Schweizer, F.; Zelenitsky, S.; Lagacé-Wiens, P. R.; Denisuik, A.; Rubinstein, E.; Gin, A. S.; Hoban, D. J.; Lynch, J. P. Drugs 2013, 73 (2), 159−177. (5) Coleman, K. Curr. Opin. Microbiol. 2011, 14 (5), 550−555. (6) Stachyra, T.; Péchereau, M. C.; Bruneau, J. M.; Claudon, M.; Frère, J. M.; Miossec, C.; Coleman, K.; Black, M. T. Antimicrob. Agents Chemother. 2010, 54 (12), 5132−5138. (7) NXL104 Inhibition of β-lactamases[C]. CHI-San Diego Challenge of Antibacterial Drug Development, 2007. (8) Lahiri, S. D; Mangani, S.; Durand-Reville; Benvenuti, M.; De Luca, F.; Sanyal, G.; Docquier, J. D. Antimicrob. Agents Chemother. 2013, 57 (6), 2496−2505. (9) (a) Bonnefoy, A.; Dupuis-Hamelin, C.; Steier, V.; Delachaume, C.; Seys, C.; Stachyra, T.; Lampilas, M. J. Antimicrob. Chemoth. 2004, 54 (2), 410−417. (b) US FDA. FDA approves new antibacterial drug Avycaz [EB/OL] [ 2014-02-25 ]. (10) MacVane, S. H.; Crandon, J. L.; Nichols, W. W.; Nicolau, D. P. Antimicrob. Agents Chemother. 2014, 58 (11), 6913−6919. (11) Ehmann, D. E.; Jahić, H.; Ross, P. L.; Gu, R. F.; Hu, J.; DurandRéville, T. F. J. Biol. Chem. 2013, 288 (39), 27960−27971. (12) (a) Aszodi, J.; Rowlands, D. A.; Mauvais, P.; Collette, P.; Bonnefoy, A.; Lampilas, M. Bioorg. Med. Chem. Lett. 2004, 14 (10), 2489−2492. (b) Versporten, A.; Bolokhovets, G.; Ghazaryan, L.;

272

DOI: 10.1021/acs.oprd.7b00290 Org. Process Res. Dev. 2018, 22, 267−272