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Trans-sulfuric acid mono- { 2-[5-(2-methylamino-ethyl)-[l,3,4]-oxadiazol-2-yl]-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl} ester.

CAS 1824664-22-3

MW 347.35, C11 H17 N5 O6 S

Beta lactamase inhibitor

To treat

Bacterial infection

Several l,6-diazabicyclo[3.2.1]octan-7-one derivatives have been described as antibacterial agents in PCT International Patent Application No. PCT/IB2012/054296. A compound of Formula (I), chemically known as irans-sulfuric acid mono- {2- [5 -(2-methylamino-ethyl)-[l,3,4]-oxadiazol-2-yl]-7-oxo-l,6-diazabicyclo[3.2.1]oct-6-yl} ester has antibacterial properties and is also disclosed in PCT International Patent Application No. PCT/US2013/034562




(VII) Formula (I)

Scheme 1


Example 1

Synthesis of traras-sulfuric acid mono-{2-[5-(2-methylamino-ethyl)-[l,3,4]-oxadiazol- 2-yl]-7-oxo-l,6-diazabicyclo[3.2.1]oct-6-yl} ester (I)

Step 1; Preparation of tr «s-{3-[N’-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane-2-carbonyl)-hydrazino]-3-oxo-propyl}-methyl-carbamic acid fert-butyl ester (IV):

Sodium salt of 6-benzyloxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (III) (5.9 g, 0.02 mol; prepared using a method disclosed in Indian Patent Application No 699/MUM/2013) was dissolved in water (100 ml) to obtain a clear solution under stirring at 25°C. To the clear solution was added successively, (3-hydrazinocarbonyl-ethyl)-methyl-carbamic acid tert-buty\ ester (II) (4.5 g, 0.02 mol), EDC. HC1 (5.7 g, 1.5 mol), and HOBt (2.7 g, 0.02 mol) followed by water (20 ml) under stirring at 25°C. The reaction mixture was stirred at 30°C for 20 hours. As maximum precipitation was reached, thin layer chromatography (acetone: hexane, 35:65) showed completion of reaction. The suspension was filtered under suction and the wet cake was washed with additional water (100 ml) and dried under vacuum at 45°C to furnish 5.5 g of ir ns-{3-[N’-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazino]-3-oxo-propyl}-methyl-carbamic acid tert-buty\ ester (IV) as a white powder in 58% yield.


Mass: 476.4 (M+l); for Molecular Formula: C23H33N5O6 and Molecular Weight:


1H NMR (CDCI3): δ 7.43-7.35 (m, 5H), 5.04 (d, 1H), 4.90 (d, 1H), 4.01 (d, 1H), 3.54 (t, 2H), 3.33 (br s, 1H), 3.14-3.07 (m, 2H), 2.85 (s, 3H), 2.53 (br s, 2H), 2.33-2.30 (m, 1H), 2.07-1.94 (m, 2H), 1.64-1.61 (m, 4H), 1.40 (s, 9H), 1.25-1.17 (m, 2H).

Step 2: Preparation of tr «s-{2-[5-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]oxadiazol-2-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (V):

To a solution of triphenylphosphine (3.3 g, 0.0126 mol) in dichloromethane (70 ml) at was added iodine (3.2 g, 0.0126 mol) and triethyl amine (7.0 ml, 0.0525 mol) under stirring at 25°C. Separately prepared solution of ir ns-{3-[N’-(6-benzyloxy-7-oxo-1 ,6-diaza-bicyclo[3.2.1 ]octane-2-carbonyl)-hydrazino] -3-oxo-propyl)-methyl-carbamic acid tert-butyl ester (IV) (5.5 g, 0.0105 mol) dissolved in dichloromethane (30 ml) was added to above reaction mixture and the mixture was stirred at 25°C for 30 minutes. The reaction mixture was concentrated and to this ethyl acetate (100 ml) was added. The separated triphenylphosphine oxide was filtered off. The filtrate was concentrated and the residue purified by silica gel column chromatography using mixture of ethyl acetate and hexane, to afford 5 g of the titled compound.


Mass: 458.3 (M+l); for Molecular Formula: C23H31N5O5 and Molecular Weight:


1H NMR (CDCI3): δ 7.44-7.35 (m, 5H), 5.04 (d, 1H), 4.93 (d, 1H), 4.70 (t, 1H), 3.62 (br s, 2H), 3.36 (s, 1H), 3.07 (t, 2H), 2.93 (br d, 1H), 2.85 (br s, 4H), 2.32-2.27 (m, 2H), 2.12 (br d, 2H), 1.95 (br s, 1H), 1.40 (s, 9H).

Step 3: Preparation of traras-{2-[5-(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]oxadiazol-2-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (VI):

To a solution of trans-{2-[5-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]oxadiazol-2-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (V) (5 g, 0.0109 mol) in methanol (50 ml) was added 10% palladium on carbon (1.5 g) at 25°C. The reaction mixture was stirred under 1 atmospheric pressure of hydrogen at 35°C for 2 hours. The catalyst was removed by filtering the reaction mixture under suction over a celite bed. The celite bed was washed with methanol (50 ml). The combined filtrate was evaporated under vacuum below 35°C to provide 3.8 g of trans- {2- [5-(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]oxadiazol-2-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (VI) in 93% yield; it was used as such for the next reaction.

Step 4: Preparation of trans -tetrabutyl ammonium salt-methyl-{2-[5-(7-oxo-6-sulphooxy-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]oxadiazol-2-yl]-ethyl}-carbamic acid tert-butyl ester (VII):

A solution of trans-{2-[5-(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[1,3,4] oxadiazol-2-yl] -ethyl }-methyl-carbamic acid tert-butyl ester (VI) (3.8 g, 9.8 mmol), in dichloromethane (38 ml) was charged with triethylamine (2.6 ml, 19.7 mmol) under stirring to provide a clear solution. To this clear solution was added sulfur trioxide -pyridine complex (2.35 g, 14.8 mmol) under stirring at 30°C. The reaction mixture was stirred for 3 hours and to this 0.5 M aqueous potassium dihydrogen phosphate (38 ml) was added followed by ethyl acetate (76 ml). The biphasic mixture was stirred for 15 minutes at 30°C. Aqueous layer was separated and re-extracted with dichloromethane and ethyl acetate mixture (1:2 v/v, 76 ml twice). To the aqueous layer was added solid tetrabutyl ammonium hydrogen sulfate (3 g, 8.8 mmol) and stirring was continued for 1

hour at room temperature. The reaction mixture was extracted with dichloromethane (3 x 50 ml). Layers were separated and dichloromethane layer dried over sodium sulfate and then evaporated under vacuum at 35°C to provide 2.8 g of irans-tetrabutyl ammonium salt-methyl- {2-[5-(7-oxo-6-sulphooxy-l,6-diaza-bicyclo[3.2. l]oct-2-yl)-[l, 3, 4]oxadiazol -2-yl] -ethyl} -carbamic acid tert-buty\ ester (VII). This was purified by column chromatography to afford 2.0 g of pure product in 29% yield.


Mass: 446.5 (M-l) as free sulfonic acid; for Molecular Formula:

(C4H9)4 and Molecular Weight: 688.5;

1H NMR (CDC13): δ 4.67 (d, 1H), 4.36 (br s, 1H), 3.33-3.29 (m, 8H), 3.23 (d, 1H), 3.08 (t, 2H), 2.87 (s, 3H), 2.83 (s, 1H), 2.28-2.22 (m, 3H), 2.07-2.00 (m, 8H), 1.50-1.41 (m, 17H), 1.28 (s, 3H), 1.01 (t, 12 H), 1.41-1.52 (m, 10 H).

Step 5: traras-sulfuric acid mono-{2-[5-(2-methylamino-ethyl)-[l,3,4]-oxadiazol-2-yl]-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl} ester:

irans-Tetrabutyl ammonium salt-methyl- {2-[5-(7-oxo-6-sulphooxy- 1 ,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]oxadiazol -2-yl] -ethyl} -carbamic acid tert-butyl ester (VII) (2.0 g, 2.9 mmol) was dissolved in dichloromethane (5 ml) and to the clear solution was slowly added trifluoroacetic acid (5 ml) at 0 to -10 °C. The reaction mixture was stirred at 0 to -10 °C for 1 hour. The solvent and excess trifluoroacetic acid was evaporated under vacuum below 40°C to approximately 1/3 of its original volume to provide pale yellow oily residue. The oily residue was stirred with diethyl ether (100 ml) for 10-15 minutes. The suspension formed was filtered under suction to provide a solid. This process was repeated twice. The solid was charged in a round bottom flask and to it was added dichloromethane (100 ml). The suspension was stirred for 15 minutes and filtered under suction to provide a solid. The obtained solid was dried under vacuum below 40°C to furnish 850 mg of trans- sulfuric acid mono-{2-[5-(2-methylamino-ethyl)-[l,3,4]-oxadiazol-2-yl]-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl} ester as white solid in 85% yield.


Mass: 346.3 (M-1) as a free sulfonic acid; for Molecular Formula: C11H17N5O6S and Molecular Weight: 347.35;

NMR (D20): δ 4.74 (d, IH), 4.16 (br s, IH), 3.45 (t, 2H), 3.31 (t, 2H), 3.15 (d, IH), 2.91 (d, IH), 2.98 (s, 3H), 2.27-2.22 (m, IH), 2.16-2.11 (m, 2H), 1.94-1.91 (m, IH);

Purity as determined by HPLC: 95.56%.




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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 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, 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 Open superstar 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 30 year tenure till date Dec 2017, Around 35 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, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , 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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