FIELD OF THE INVENTION:
The present invention relates to improved, safe and industrially feasible process for preparing sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl] sulfate. The present invention also discloses new intermediate and its process for preparation.
BACKGROUND OF THE INVENTION:
Avibactam sodium, sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl] sulfate of formula-1 is a non-p-lactam p-lactamase inhibitor.

It is developed by Actavis (now Teva) jointly with AstraZeneca. Avibactam in combination with ceftazidime to treat complicated urinary tract (cUTI) and complicated intra-abdominal infections (cIAI) caused by antibiotic resistant-pathogens, including those caused by multi¬drug resistant Gram-negative bacterial pathogens and sold under the brand name Avycaz.
US 7,112,592 discloses novel heterocyclic compounds and their salts. US’592 also discloses methods of using the compounds as antibacterial agents.
WO 200210172 describes the production of azabicyclic compounds and salts thereof with acids and bases.
US 20100197928 discloses methods for. preparing 2,5-disubstituted piperidine and novel intermediates.
The main disadvantage of prior art processes is poor yield with poor purity.
Hence it is needed to develop improved process for preparing sodium [(2S,5R)-2-carbamoyl- 7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl] sulfate with higher yield and higher purity.
The present invention provides improved process for preparation of sodium [(2S,5R)-2- carbamoyl-7-oxo-1,6-diazabicyclo[3.2. l]octan-6-yl] sulfate.
SUMMARY OF THE INVENTION:

The present invention relates to robust, eco-friendly and effective process for the preparation of sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl] sulfate of formula-1
o
. ' ‘A^ . '
H2N
N^l O
NS ^S-ONa
0 °n
Formula-1
One embodiment of the present invention provides process for preparing of (2S,5R)-6- (benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide of formula-3 comprises;
o
Formula-3
(a) reacting sodium (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1 ]octane-2- carboxylate of formula-2 with coupling agent in presence of base, solvent
(b) amidating with amidating agent
(d) isolating (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1 ]octane-2-carboxamide
One embodiment of the present invention provides process for preparing of trans-7-oxo-6- (sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide of formula-5 comprises;
o
A^
H2N Y
M o
J^S-ONBU4 o oil
0
Formula-5
(a) debenzylating (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1 ]octane-2-carboxamide in presence of debenzylating agent, hydrogen source, SO3 complex, solvent

(b) sulfonating formula-4 in presence of phase transfer catalyst, buffer, solvent
(c) isolating trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide
One embodiment of the present invention provides process for preparing of sodium [(2S,5R)- 2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl] sulfate of formula-1 comprises; -

(a) converting trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide to a pharmaceutically acceptable salt in presence of the ion exchange resin, solvent
(b) isolating sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl] sulfate
/
BRIEF DESCRIPTION OF DRAWINGS:
l.lH NMR(CDCh) spectrum of (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane- 2-carboxamide
2. Mass spectrum of (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicycIo[3.2.1]octane-2- carboxamide
3. 'H NMR(CDCb) spectrum of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2- carboxamide
4. Mass spectrum of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide
5. *H NMR(CDCb) spectrum of sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6- diazabicyclo[3.2.1]octan-6-yl] sulfate
6. Mass spectrum of sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl] sulfate

OBJECT OF THE INVENTION:
(1) one object of the present invention is to provide improved and simple process which results in higher purity.
(2) Another object of the present invention is to provide new intermediate named TEA sulphur trioxide salt.
(3) Another object of the present invention is to provide higher yield.
(4) Another object of the present invention is to provide environment friendly process. DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to improved, effective, economical and industrially applicable process for the preparation of sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6-
diazabicyclo[3.2.1]octan-6-yl] sulfate of formula-1

One aspect of the present invention provides process for preparing of (2S,5R)-6-(benzyloxy)- 7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide of formula-3 comprises;

- (a) reacting sodium (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-
carboxylate of formula-2 with coupling agent in presence of base, solvent
(b) amidating with amidating agent
(d) isolating (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide

The solvent used for step (a) is selecting from the group consisting of dichloromethane, ethylene dichloride, or mixture thereof.
The coupling agent for step (a) is selected from the group consisting of HOBt, pivaloyl chloride, EDC hydrochloride, dic.yclohexylcarbodiimide.
The base used for step (a) is organic base selected from the group consisting of methylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide (LDA), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO), imidazole and the like or mixture thereof
The amidating agent is Con. Ammonia and the solvent for amidation reaction is water.
The solvent used for step (c) is isopropyl alcohol.
The present invention provides improved process for conversation of sodium (2S,5R)-6- (benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylate to (2S,5R)-6-(benzyloxy)-7- oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide with efficient, cost-effective reagents which results in higher yield with good purity as compare to prior art.
Prior art process gives 60% yield but present invention provides more than 78% yield.
The (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide is
characterized by lH NMR (DMSO-d6): 1.608-1.689(2H,m), 1.834-1.848(lH,m), 2.038- 2.070(1 H,m),2.90(2H,s),3.623(1 FI,s),3.678-3.695(1 H,d),4.896- 4.969(2H,dd),7.294(lH,bs),7.358-7.463(6H,m). lH NMR spectrum is depicted in Fig.l.
The (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2. l]octane-2-carboxamide is
characterized by Mass having peak at 276.2 (M+H)+. Mass spectrum is depicted in Fig.2
The SOR(0.5% in CHCh) is observed at +6.95°.
The process for preparation of (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2- carboxamide of formula-3 given in the below reaction scheme-1

One aspect of the present invention provides process for preparing of trans-7-oxo-6- (sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide of formula-5 comprises;

(a) debenzylating (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1 ]octane-2-carboxamide in presence of debenzylating agent, hydrogen source, SO3 complex, solvent
(b) sulfonating formula-4 in presence of phase transfer catalyst, buffer, solvent
(c) isolating trans-7-oxo-6-(sulphoxy)-1,6-diazabicyclo[3,2,1 ] octane-2-carboxamide
The debenzylating agent is selected from the group consisting of 5% or 10% palladium on carbon, 20% palladium hydroxide on carbon, platinum, rhodium, nickle.
The hydrogen source is hydrogen gas.
The SO3 complex is selected from the group consisting of sulphur trioxide complex, SO3 pyridine, SO3 dimethyl form amide, SO3 triethylamine, SO3 trimethylamine, chlorosulfonic acid, oleum.
The solvent is selected from the group consisting of methanol, ethanol, isopropanol, propanol, butanol, water or mixture thereof.
The Phase transfer catalyst is tetra-n-alkylammonium ion source selected from the group M eonsisting j of p tetraethyW ^ammonium chloride,- rrtetFamethylammonium—hydroxide,—

tetrabutylammonium acetate, tetrabutylammonium bisulphate, tetrabutyl ammonium hydrogen sulfate.
‘ The buffer is sodium dihydrogen phosphate.
The solvent for sulfonation is acetic acid.
The solvent for isolation is selected from the group consisting of MIBK, acetone, isopropyl acetate, ethyl acetate, dichloromethane.
The present invention provides a new intermediate- TEA sulphur trioxide salt. The formation of TEA sulphur trioxide salt results in good yield with good purity as compare to prior art. TEA sulphur trioxide salt reacts with phase transfer catalyst for nBu4 derivatives which gives good yield of (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide.
The (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide is
characterized by lH NMR (DMSO-d6): 0.991-1.027(12H,t),1.409-1.501(8H,m), 1.637- 1.71 l(9H,m),1.822-1.905 (lH,m), 2.159(lH,m), 2.365-2.419(lH,dd),2.836-2.866(lH,d), 3.908-3.928(lH,d), 4.363(lH,s), 5.467(lH,s) 6.644(lH,s). lH NMR spectrum is depicted in Fig.3.
The (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide is
characterized by Mass having peak at 264.19 (M+H)+. Mass spectrum is depicted in Fig.4
The SOR(0.5% in MeOH) is observed at -31.79°.
The process for preparation of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyc!o[3,2,l] octane-2- carboxamide of formula-5 given in the below reaction scheme-2

One aspect of the present invention provides process for preparing of sodium [(2S,5R)-2- carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl] sulfate of formula-1 comprises;

(a) converting trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide to a pharmaceutically acceptable salt in presence of the ion exchange reagent, solvent
(b) isolating sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl] sulfate The ion exchange reagent is sodium-2-ethyl hexanoate.
The solvent is selected from the group consisting of methanol, ethanol, isopropanol, propanol, butanol, water or mixture thereof.
The (2S,5R)-6-(benzyloxy)-7-oxo-.l,6-diazabicyclo[3.2.1]octane-2-carboxamide is
characterized by 'H NMR (DMSO-d6): 1.584-1.697(2H,m),1.836-1.845(lH,m),2.023- 2.072(1 H,m),2.908-2.937(1 H,d),3.005-3.034(1 H,d),3.677-
3.693(lH,d),3.98(lH,s),7.292(lH,s),7.441(lH,s). 'H NMR spectrum is depicted in Fig.5.
The (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1 ]octane-2-carboxamide is
characterized by Mass having peak at 264.21 (M+H)+. Mass spectrum is depicted in Fig.6
The SOR(0.5% in water) is observed at -50.242°.
The process for preparation of sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6- diazabicyclo[3.2.1]octan-6-yl] sulfate of formula-1 given in the below reaction scheme-3

The following examples explain various other embodiments without limiting the scope of the present invention.
Example-1: Preparation of (2S, 5R)-6-(benzyloxy)-7-oxo-l, 6-diazabicyclo[3.2.1]octane- 2-carboxamide
To the suspension- of DCM, TEA and sodium (2S, 5R)-6-(benzyloxy)-7-oxo-l,6- diazabicyclo[3.2.1]octane-2-carboxy!ate, Pivaloyl chloride was added at 0 - 5 °C. The reaction mixture stirred for 30 min. The reaction monitored by TLC to ensure conversion of sodium (2S, 5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1 ]octane-2-carboxylate. Mass . was cooled to -20 °C and purged ammonia gas for 15 min followed by stirred the mass for 30 min. The reaction quenched with water and product extracted with dichloromethane. The organic layer distilled off under vacuum and Isolated the solid from isopropylalcohol.
HPLC Purity: 99.6%
SOR(0.5% in water) : +6.95°
Example-2: Preparation of Tetrabutylammoniumsalt of trans-7-oxo-6-(sulphoxy)-l,6- diazabicyclo[3,2,l] octane-2-carboxamide
To the suspension of isopropylalcohol, Water, triethylamine and (2S, 5R)-6-(benzyloxy)-7- oxo-1, 6-diazabicyclo[3.2.1]octane-2-carboxamide, TEA.SO3 and Pd/C added at room temperature. Stirred reaction mixture for 20 min. Applied hydrogen gas pressure to the mass for 5h at room temperature. The reaction monitored by TLC. Filtered the mass through hyflo to remove catalyst. The pH of reaction mass adjusted by Sodium dihydrogen phosphate and washed the mass with Ethyl acetate. Tetra butyl ammonium hydrogen sulphate added to the mass and stirred for 30 min. The product extracted with DCM and organic layer distilled off under vacuum. The solid collected from Methyl isobutyl ketone.
HPLC Purity: 99.55%
SOR(0.5% in methanol): -31.79°
Example-3: Preparation of Tetrabutylammoniumsalt of trans-7-oxo-6-(sulphoxy)-l,6- diazabicyclo[3,2,l] octane-2-carboxamide
To the suspension of isopropylalcohol, Water, triethylamine and (2S, 5R)-6-(benzyloxy)-7- oxo-1, 6-diazabicyclo[3.2.1 ]octane-2-carboxamide, TEA.SO3 and Pd/C added at room temperature. Stirred reaction mixture for 20 min. Applied hydrogen gas pressure to the mass for 5h at room temperature. The reaction was monitor by TLC. Filter the mass through hyflo to remove catalyst. The pH of reaction mass adjusted by Added acetic acid and washed the

mass with Ethyl acetate. Tetra butyl ammonium acetate solution added and stirred the mass for 30 min. The product extracted with DCM and organic layer distilled off under vacuum. The solid collected from Methyl isobutyl ketone.
HPLC purity: 99.62 % .
SOR(0.5% in methanol): -31.20°
Example-4: Preparation of sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6-
diazabicyclo[3.2.1]octan-6-yl] sulfate
To the solution of Ethanol, Tetrabutylammoniumsalt of trans-7-oxo-6-(sulphoxy)-l,6- diazabicyclo[3,2,l] octane-2-carboxamide, Sodium 2-Ethyl hexanoate in Ethanol added slowly over the period of 4h at room temperature and stirred reaction mixture for 2h. Filtered the solid and washed with Ethanol.
HPLC purity: 99.8%
SOR(0.5% in water) : -50.242°