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CB-618, CB-238618

CAS 1463520-70-8
C8 H10 N4 O6 S, 290.25
Sulfuric acid, mono[(1R,2S,5R)-2-(1,3,4-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester
(25, 5R)-sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester

SODIUM SALT

sodium salt of (2S,5R)-sulfuric acid mono-(2-[1,3,4]oxadiazol-2-yl-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl)ester

CAS 1628207-16-8
C8 H10 N4 O6 S . Na
Sulfuric acid, mono[(1R,2S,5R)-2-(1,3,4-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester, sodium salt (1:1)
PATENTS

WO2013149121

US 20140275001

US 20150094472

WO 2016081452

Infection, multidrug resistant bacteria (MDR) in  phase 1 at  Merck
CB-618 is in phase I clinical trails by Cubist for the treatment of resistant bacterial infections, including carbapenem-resistant Enterobacteriaceae and Klebsiella pneumonia carbapenemases infection.

CB-618 is a beta-Lactamase inhibitor in phase I clinical trials at Merck & Co. for the treatment of multidrug resistant bacterial infections, including those caused by carbapenem-resistant Enterobacteriaceae and Klebsiella pneumoniae carbapenemases.

The product was originally developed at Cubist. In 2015, Merck & Co. acquired the company

  • Originator Cubist Pharmaceuticals
  • Class Antibacterials
  • Mechanism of Action Beta lactamase inhibitors

Highest Development Phases

  • Phase I Gram-negative infections

Most Recent Events

  • 01 Apr 2015 Cubist Pharmaceuticals completes a phase-I clinical trial in Gram-negative infections in USA (IV) (NCT02341599)
  • 21 Jan 2015 Cubist Pharmaceuticals has been acquired by Merck & Co
  • 14 Jan 2015 Phase-I clinical trials in Gram-negative infections in USA (IV)

Bacterial resistance to β-lactam antibiotics, especially in Gram-negative bacteria, is most commonly mediated by β-lactamases. β-lactamases are enzymes that catalyze the hydrolysis of the β-lactam ring, which inactivates the antibacterial activity of the β-lactam antibiotic and allows the bacteria to become resistant. Inhibition of the β-lactamase with a BLI slows or prevents degradation of the β-lactam antibiotic and restores β-lactam antibiotic susceptibility to β-lactamase producing bacteria. Many of these β-lactamases are not effectively inhibited by BLIs currently on the market rendering the β-lactam antibiotics ineffective in treating bacteria that produce these β-lactamases. There is an urgent need for novel BLIs that inhibit β-lactamases that are not effectively inhibited by the current clinical BLIs (e.g. KPC, class C and class D β-lactamases) and that could be used in combination with β-lactam antibiotics to treat infections caused by β-lactam resistant bacteria.

PATENT

WO2013149121

Yu Gui Gu, Yong He, Ning Yin, Dylan C. ALEXANDER, Jason B. CROSS, Chester A. Metcalf, Robert Busch
Applicant Cubist Pharmaceuticals, Inc.

Example 3: Synthesis of (2S,5R)-2-(l ,3,4-oxadiazol-2-yl)-7-oxo-l ,6- diazabicyclo[3.2.1 loctan-6-yl hydrogen sulfate (Compound 701 )

Figure imgf000068_0001

Step 1: Ι,Γ-Carbonyldiimidazole (5.8 g, 36.2 mmol) was added to a 0 °C solution of (2S,5R)- 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (5.0 g, 18.1 mmol) in dry THF (200 mL). The reaction mixture was allowed to warm to rt then was stirred at rt for 3 hrs. Formohydrazide (5.4 g, 90.5 mmol) was added in one portion, and the reaction mixture was stirred for additional 3 hrs. The mixture was then diluted with saturated sodium chloride and exatracted with EtOAc (3x). The combined organic layer was washed with saturated sodium chloride (2x), dried over Na2S04, and concentrated to afford crude (25,5 ?)- 6-(benzyloxy)-N-formyl-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (-11 g), which was directly used in the next step. ESI-MS (Ef , m/z): 319.1 [M+H]+.

Step 2: To a -10 °C solution of (25′,5«)-6-(benzyloxy)-N-formyl-7-oxo-l,6- diazabicyclo[3.2.1]octane-2-carbohydrazide (11 g) in dry DCM (200 mL) was added pyridine (28 mL), followed by dropwise addition of (CF3S02)20 (28 mL). The reaction mixture was allowed to warm to rt and was stirred for 3 hrs. The reaction mixture was then cooled to -10 °C and quenched with sat. NaHCC>3. The organic layer was separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layer was dried over Na2S04, concentrated and purified by silica gel column chromatography (gradient elution 1 :3 to 2: 1 EtOAc/hexanes) to give (25,5/?)-6-(benzyloxy)-2-(l,3,4-oxadiazol-2-yl)-l ,6- diazabicyclo[3.2.1]octan-7 -one (4.6 g, 86% for two steps) as a slightly yellow solid. ESI-MS (EI+, m/z): 301.0 [M+H]+.

Step 3: To a solution of (25,5/?)-6-(benzyloxy)-2-(l,3,4-oxadiazol-2-yl)-l ,6- diazabicyclo[3.2.1]octan-7-one (4.6 g, 15.3 mmol) in THF (150 mL) was added 10% Pd/C (1 g). The mixture was stirred under H2 atmosphere at rt for 3 hrs. The reaction mixture was then filtered and concentrated to afford (25,5/?)-6-hydroxy-2-(l,3,4-oxadiazol-2-yl)-l,6- diazabicyclo[3.2.1]octan-7-one (2.9 g, 91 %), which was used directly in the next step. ESI- MS (EI+, m/z): 211.1 [M+H]+. Step 4: To a solution of (25,5fl)-6-hydroxy-2-(l,3,4-oxadiazol-2-yl)-l,6- diazabicyclo[3.2.1]octan-7-one (2.9 g, 13.8 mmol) in dry pyridine (60 mL) was added SC>3- Py (11.0 g, 69.0 mmol). The reaction mixture was stirred at rt for 8 hrs and then concentrated under vacuum. The residue was re-dissolved in aqueous NaH2PC>4 (1.5 M, 100 mL) then tetrabutylammonium hydrogensulphate (5.88 g, 17.3 mmol) was added. The mixture was stirred at rt for 20 minutes, then was extracted with EtOAc (4x). The combined organic layer was dried and concentrated and the residue was purified by silica gel column chromatography (gradient elution 10:1 to 2:1 DCM/acetone) to afford tetrabutylammonium (25,5/?)-2-(l ,3,4-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl sulfate (4.1 g, 97%) as a white solid. ESI-MS (EL, m/z): 289.0 [M-H]\ lH NMR (400 MHz, CDC13): δ 8.48 (s, 1H), 4.75 (d, / = 6.5 Hz, 1H), 4.40 (br s, 1H), 3.34-3.26 (m, 9H), 2.82 (d, / = 12.0 Hz, 1H), 2.37-2.25 (m, 3H), 2.06-1.98 (m, 1H), 1.71-1.65 (m, 8H), 1.49-1.42 (m, 8H), 1.01 (t, / = 7.5 Hz, 12H).

Step 5: Resin Exchange: Tetrabutylammonium (25, 5R)-2-(l, 3, 4-oxadiazol-2-yl)-7-oxo-l, 6-diaza-bicyclo[3.2.1]octan-6-yl sulfate (4.1 g, 7.72 mmol) was dissolved in a minimum amount of HPLC grade water (~ 40 mL) and passed through a column of 80 g of DOWEX 50WX 8 Na+ resin (the resin was prewased with >4 L of HPLC grade water) and eluted with HPLC grade water to afford sodium (25,5fl)-2-(l,3,4-oxadiazol-2-yl)-7-oxo-l,6- diazabicyclo[3.2.1]octan-6-yl sulfate (2.2 g, 91 %) as a white solid after lyophilization. ESI- MS (EI+, m/z): 291.2 [M+H]+. lH NMR (300 MHz, D20) δ 8.92 (s, 1H), 4.84 (d, J = 6.1 Hz, 1H), 4.20 (br s, 1H), 3.25-3.16 (m, 1H), 2.92 (d, / = 12.3 Hz, 1H), 2.41-2.26 (m, 1H), 2.26- 2.11 (m, 2H), 2.04-1.89 (m, 1H).

PATENT

WO-2016157057

Wockhardt Ltd

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016157057&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

A compound of Formula (I), chemically known as sodium salt of 2S, 5R) mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diazabicyclo[3.2.1 ]oct-6-yl)ester has antibacterial properties and is disclosed in PCT International Patent Application No. PCT/US2013/034562. The compound of Formula (I) is also generically disclosed in PCT International Patent Application No. PCT/IB2012/054296. The present invention discloses a process for preparation of a compound of Formula (I).

Formula (I)

Scheme 1.

(VI) Compound of Formula (I)

Example 1

Sodium salt of (25, 5R) sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester

Step I: Synthesis of (25,5R)-2-(iV’-formyl-hydrazinocarbonyl)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (III):

To a turbid solution of sodium salt of (2<S’,5i?)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1 ] octane-2-carboxylic acid (II, 20 g, 0.067 mol) (prepared according to process disclosed in PCT/IB2013/059264) in dimethylformamide (200 ml) was added EDC hydrochloride (19.44 g, 0.10 mol) followed by formyl hydrazide (4.02 g, 0.067 mol) and N-hydroxybenzotriazole (9 g, 0.67 mol) at about 25°C under stirring. Diisopropylethylamine (35.62 ml, 0.20 mol) was added to the reaction mixture and stirred at 25°C temperature for 18 hours. The reaction mixture was evaporated under vacuum to provide a residue. The residue was dissolved in ethyl acetate (500 ml) and washed with water (500 ml χ 2), followed by saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulphate and evaporated under vacuum to provide a crude intermediate, which was purified by silica gel column chromatography to provide 11 g of the titled compound as solid in 52% yield.

Analysis:

Mass: 319.1 (M+l); for Molecular Formula of C15H18N4O4 and Molecular Weight of 318.34;

H1 NMR (DMSO-d6): δ 9.93 (s, 1H), 9.87 (s, 1H), 8.01 (s, 1H), 7.36-7.46 (m, 5H), 4.91-4.97 (dd, 2H), 3.83-3.84 (br s, 1H), 3.70 (s, 1H), 3.15-3.18 (br s, 1H), 2.90-2.95 (m, 1H), 1.99-2.03(m, 1H), 1.86(br s, 1H), 1.73-1.75 (m, 1H), 1.66 (m, 1H).

Step II: Synthesis of (25,5R)-2-([l,3,4]-oxadiazol-2-yl)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (IV):

To a clear solution of (2<S’,5i?)-2-(N’-formyl-hydrazinocarbonyl)-6-benzyloxy-7-oxo-l ,6-diaza-bicyclo[3.2.1 ] octane (III, 11 g, 0.0345 mol) in chloroform (120 ml) was added diisopropylethylamine (18.31 ml, 0.1035 mol) and p-tolylsulfonylchloride (9.83 g, 0.0517 mol). The solution was stirred at 60°C for 15 hours. Reaction mixture was cooled to room temperature and water (100 ml) was added. Organic layer was dried over anhydrous sodium sulphate and evaporated under vacuum to provide a crude residue, which was purified by silica gel column chromatography to provide 7 g of the titled compound as a solid in 68% yield.

Analysis:

Mass: 301.3 (M+l); for Molecular Formula of Ci5Hi6N403 and Molecular Weight of 300.32;

H1 NMR (CDC13): δ 8.45 (s, 1H), 7.25-7.44 (m, 5H), 5.07-5.10 (dd, 1H), 4.92-4.95 (dd, 1H), 4.76-4.78 (br s, 1H), 3.37 (br s, 1H), 2.93-.95 (br s, 1H), 2.75-2.77 (m, 1H), 2.32-2.33 (m, 2H), 2.13-2.16 (m, 1H), 1.93-2.01 (m, 1H).

Step III: Synthesis of (25,5R)-2-([l,3,4]-oxadiazol-2-yl)-6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (V):

To a clear solution of (2<S’,5i?)-2-([l,3,4]-oxadiazol-2-yl)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1 ] octane (IV, 7.0 g, 0.0233 mmol) in methanol (70 ml) was added 10% palladium on carbon (2.5 g). The suspension was stirred under atmospheric hydrogen pressure at a temperature 25° C for 2 hrs. The catalyst was filtered over a celite bed and the bed was washed with methanol (30 ml). The filtrate was concentrated under vacuum to provide an oily residue. The residue was triturated with cyclohexane (100 ml) to effect solid formation. The suspension was filtered under suction and the wet cake was washed with additional cyclohexane (50 ml). The soild was dried under vacuum to provide 4.5 g of the titled compound as a whitish solid in 92% yield, which was used for the next reaction immediately.

Analysis:

Mass: 211.2 (M+l); for Molecular Formula of C8Hi0N4O3 and Molecular Weight of 210.19; 1H NMR (DMSO-d6): δ 9.88 (br s, 1H), 9.29 (s, 1H), 4.65 (d, 1H ), 4.64 (br s, 1H), 2.94-2.97 (br d, 1H), 2.63-2.66 (d, 1H), 1.89-2.09 (m,3H), 1.82-1.86 (m, 1H).

Step IV: Synthesis of tetrabutylammonium salt of (25, 5R)-sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester (VI):

To a clear solution of (2<S’,5i?)-2-([l,3,4]-oxadiazol-2-yl)-6-hydroxy-7-oxo-l ,6-diaza-bicyclo[3.2.1 ] octane (V, 4.5 g, 0.0214 mol) in dichloromethane (50 ml) was added triethylamine (9 ml, 0.642 mol), followed by the addition of sulfur trioxide pyridine complex (6.83 g, 0.428 mol). The resulting reaction mixture was stirred for 2 hours. Tetrabutylammonium hydrogen sulfate (7.26 g,

0.0214 mol) was added to the reaction mixture and it was stirred for 1.5 hours. A solution of aqueous 0.5 N KH2PO4 (100 ml) was added to the reaction mixture. Layers were separated and the aqueous layer was washed with dichloromethane (125 ml). Combined organic layer was dried over Na2S04, and was evaporated under vacuum to yield crude foam, which was purified on silica gel column chromatography to give 7 g of the titled compound as white foam in 98% yield.

Analysis:

Mass: 289.1 (M-l); for Molecular Formula
and Molecular Weight of 517.26;

1H NMR (DMSO-d6): δ 9.30 (s, 1H), 4.69 (d, 1H), 4.06 (br s, 1H ), 3.14-3.18 (m, 8H), 2.94-2.97 (br d, 1H), 2.67-2.70 (d, 1H), 1.98-2.05 (m,lH), 2.85-2.92 (m, 1H), 1.53-1.60 (m, 8H), 1.27-1.36 (m, 8H), 0.91-0.95 (m, 12H).

Step V: Sodium salt of (25, 5R)-sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester (I):

The compound sodium salt of (2S, 5i?)-sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester of Formula (I) was prepared by loading tetrabutylammonium salt of sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester (VI, 7 g) on a column packed with Amberlite IR 120 Na form of resin, and by eluting the column with methanol water mixture (9: 1). Fractions containing compound were collected and solvent was evaporated under vacuum below 40°C, to provide formula- 1 compound in 4 gm (62%) quantity as a white solid.

Analysis:

Mass: 289.3 (M-l) as free acid; for Molecular Formula
and Molecular Weight 290.26;

H1 NMR (DMSO-d6): δ 9.29 (s, 1H), 4.70(d, 1H), 4.061 (d, 1H), 2.95 (d, 1H), 2.69 (d, 1H), 2.19 (m, 1H), 2.07 (m, 2H), 1.90 (m, 1H);

Purity as determined by HPLC: 89 86%;

WO2010056827A1 * Nov 12, 2009 May 20, 2010 Protez Pharmaceuticals, Inc. Beta-lactamase inhibitors
WO2010118361A1 * Apr 9, 2010 Oct 14, 2010 Sopharmia, Inc. Beta lactamase inhibitors
US20110294777 * Jan 15, 2009 Dec 1, 2011 Merck Sharp & Dohme Corp. Beta-lactamase inhibitors
Reference
1 * CROMPTON, I. E. ET AL.: “Beta-Lactamase inhibitors: The inhibition of serine beta-lactamases by specific boronic acids“, BIOCHEM. J., vol. 251, 1988, pages 453 – 459, XP055170895
2 * See also references of EP2831075A4

//////////CB-618, phase 1

O=S(=O)(O)ON3[C@H]1C[N@]([C@@H](CC1)c2nnco2)C3=O


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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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