ChemicalBook CAS DataBase List Relebactam

Relebactam synthesis

12synthesis methods

Product Name:Relebactam
CAS Number:1174018-99-5
Molecular formula:C12H20N4O6S
Molecular Weight:348.38

Relebactam, also known as MK-7655, a potent and selective β-lactamase inhibitor. At a concentration of 4 mg/L, MK-7655 reduced imipenem MICs for Enterobacteriaceae with KPC carbapenemases from 16-64 mg/L to 0.12-1 mg/L. MK-7655 potentiated imipenem against Enterobacteriaceae with KPC carbapenemases or combinations of β-lactamase and impermeability, but not those with metallo-carbapenemases. It augmented the activity of imipenem against P. aeruginosa in general and OprD mutants in particular. Synthetic Description Reference: Mangion, Ian K.; Ruck, Rebecca T.; Rivera, Nelo; Huffman, Mark A.; Shevlin, Michael. A concise synthesis of a β-lactamase inhibitor. Organic Letters. Volume 13. Issue 20. Pages 5480-5483. Journal; Online Computer File. (2011). Synthetic Description Reference: Liu, Zhijian; Yasuda, Nobuyoshi; Simeone, Michael; Reamer, Robert A. N-Boc Deprotection and Isolation Method for Water-Soluble Zwitterionic Compounds. Journal of Organic Chemistry. Volume 79. Issue 23. Pages 11792-11796. Journal; Online Computer File. (2014). Synthetic Description Reference: Wankhede, Karuna Suresh; Surwase, Mahesh Manikrao; Bhawsar, Satish; Deshpande, Prasad Keshav; Yeole, Ravindra Dattatraya; Patel, Mahesh Vithalbhai. A process for preparation of (2S,5R)- sulfuric acid mono-{[(4-aminopiperidin-4-yl) carbonyl]-7-oxo-1,6-diazabicyclo[3.2.1]-oct-6-yl}ester. Assignee Wockhardt Limited, India. IN 296654. (2018 Synthetic Description Reference: Gordon, Eric M.; Freund, John; Gallop, Mark A.; Duncton, Matthew Alexander James. Beta-lactamase inhibitors and uses thereof. Assignee Arixa Pharmaceuticals, Inc., USA. US 10085999. (2018). Synthetic Description Reference: Miller, Steven P.; Limanto, John; Zhong, Yong-Li; Yasuda, Nobuyoshi; Liu, Zhijian. Preparation of tert-butyl 4-((1R,2S,5R)-6- (benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate. Assignee Merck Sharp & Dohme Corp., USA. WO 2014200786. (2014).

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

ROUTE 4

ROUTE 5

Reference: Mangion, Ian K.; Ruck, Rebecca T.; Rivera, Nelo; Huffman, Mark A.; Shevlin, Michael. A concise synthesis of a β-lactamase inhibitor. Organic Letters. Volume 13. Issue 20. Pages 5480-5483. Journal; Online Computer File. (2011).

N,N,N-tributylbutan-1-aminium [({(2S,5R)-7-oxo-2-[(piperidin-4-ylamino)carbonyl]-1,6-diazabicyclo[3.2.1]oct-6-yl}oxy)sulfonyl]oxidanide

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Yield:1174018-99-5 83.8%

Reaction Conditions:

Stage #1: tetrabutyl ammonium salt (25,5R)-4-tert-butyl{(6-sulfooxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-ylcarbonyl)amino}piperidine-1-carboxylatewith tetrafluoroboric acid in 2,2,2-trifluoroethanol at 18 - 22; for 12.1833 h;
Stage #2: with sodium hydrogencarbonate in dichloromethane;2,2,2-trifluoroethanol;water at 18.5; pH=4.5;Product distribution / selectivity;

Steps:

1C.12

The solution of Bu4N⁺OSθ3 salt in TFE (34 L) was used as received from the prior step with an assumed yield of 100%. The reaction mixture was cooled in an ice bath, and HBF4-Et2θ (1.57 L) was added via addition funnel over 11 minutes between 18⁰C and 22⁰C.The resulting white slurry was allowed to stir overnight (12 hours). TFE (-15 L) was removed by vacuum distillation. DCM (15 L) was then added. To a 100-L extractor was charged pyrogen-free water (35 L) and NaHCθ3 (274 g), and the solution was cooled to 13°C. The reaction mixture was transferred by vacuum into the extractor with temperature of 11-13⁰C. The reaction flask was rinsed with additional DCM (5 L) and the suspension also transferred to the extractor. The reaction mixture was warmed to 18.5 ⁰C and de-pyrogenated water (12 L) was added to solubilize all the solids. The final pH was 4.5. The organic layer was separated, and the aqueous layer was washed with DCM (2 x 16 L). Assay of the aqueous layer showed 2.38 kg (83.8 %)The aqueous layer was charged to a clean flask. The solution was concentrated by vacuum distillation followed by azeotropic distillation with IPA. At this time, lH NMR analysis of the IPA:H2θ ratio indicated the presence of 13.4 L of water and 24.6 L of IPA. IPA (22 L) was added. The white crystalline solid was filtered and washed with 7:1 IPA:de-pyrogenated water (16 L) and dried under vacuum and nitrogen at room temperature to afford the title product in the form of a crystalline channel hydrate, 1.5 wt% water. (Yield = 1.715 kg, 57.4% over Steps 11 and 12). ¹H NMR (400 MHz₅ DMSOd₆ ): 8.3 (br s, 2H)₅ 8.21 (d, J- 7.8 Hz, IH), 4.01(s, IH), 3.97-3.85 (m, IH), 3.75 (d, J= 6.5 Hz, IH) 3.28(dd, J= 12.9, 2.5 Hz, 2H) 3.05-2.93(m, 4H), 2.08-1.97(m, IH), 1.95-1.79(m, 3H), 1.75-1.59(m, 4H)

References:

WO2009/91856,2009,A2 Location in patent:Page/Page column 71-72