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 (cUTl) and complicated intra-abdominal infections (cIAl) caused by antibiotic resistant-pathogens, including those caused by multidrug 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 ofsodium [(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1 ]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-
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-carboxamideof 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
(c) isolating (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide
One another embodiment of the present invention provides process for preparing of tri butyl ammonium salt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide of formula-4 comprises;
(a) debenzylating (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide in presence of debenzylating agent, hydrogen source, SO3 complex, solvent
(b) isolating tri butyl ammonium salt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide
0 0
One another 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 tri butyl ammonium salt of 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
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 Tri butyl ammonium salt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyc!o[3,2,l] octane-2-carboxamide (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-1,6-diazabicyclo[3.2.1 ]octane-2-carboxamideof 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
(c) 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, dicyclohexylcarbodiimide.
The base used for step (a) is organic base selected from the group consisting of diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM),2,6-lutidine, 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 andthe 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 process for preparation of (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamideof formula-3given in the below reaction scheme-1
One aspect of the present invention provides process for preparing of tri butyl ammonium salt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide of formula-4
comprises;
(a) debenzylating (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1 ]octane-2-carboxamidein presence of debenzylating agent, hydrogen source, SO3 complex, solvent (b) isolating tri butyl ammonium salt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] 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, nickel.
The hydrogen source is hydrogen gas.
The SO3 complex is selected from the group consisting of sulphur trioxide complex, SO3 pyridine, SO3 dimethylformamide, SO3 triethylamine, SO3 trimethylamine, tributylsulfoammonium betaine, chlorosulfonic acid, oleum.
The solvent is selected from the group consisting of MIBK, acetone, isopropyl acetate, ethyl acetate, dichloromethane mixture thereof.
The solvent for sulfonation is acetic acid.
The present invention provides a new intermediate- tri butyl ammonium salt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide.The formation of tri butyl ammonium salt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide results in good yield with good purity.
The process for preparation of tri butyl ammonium salt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide of formula-4 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 tri butyl ammonium salt of 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-ethylhexanoate.
The solvent is selected from the group consisting of methanol, ethanol, isopropanol, propanol, butanol, water or mixture thereof.
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.
Examplc-1: Preparation of(2S, 5R)-6-(benzyloxy)-7-oxo-l, 6-diazabicyclo[3.2.1]octane-2-
carboxamidc * *
To the suspension of DCM, TEA and sodium (2S, 5R)-6-(benzyloxy)-7-oxo-l,6- diazabicyclo[3.2.1]octane-2-carboxylate, 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%
Example-2: Preparation of Tri butyl ammonium salt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,1] octane-2-carboxamide To the solution of DCM, TBA and (2S, 5R)-6-(bcnzyloxy)-7-oxo-l, 6- diazabicyclo[3.2.1]octane-2-carboxamide. TBA.SO3 and 10 % w/w Pd/C added at rt and stirred reaction mixture for 20 min. Applied hydrogen gas pressure to the mass for 12h. The reaction monitored by TLC, filtered the mass through hyflo to remove catalyst. The filtrate mL washed with water. The resulting organic layer distilled off under vacuum to get Tri butyl ammonium salt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide as
oil.
HPLC Purity: 88%
Example-3: Preparation of sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1 ]octan-6-yl] sulfate
To the solution of Ethanol, Tributylammoniumsalt of trans-7-oxo-6-(suiphoxy)-l,6- diazabicyclo[3,2,l] octane-2-carboxamide, Sodium 2-Ethyl hexanoatein Ethanoladded slowly over the period of 4h at room temperature and stirred reaction mixture for 2h. Filtered the solid and washed with Ethanol.
HPLC purity: 99.3%
We Claim,
1. A process for preparing sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl] sulfate of formula-1 comprising;
O
o^NolONa
0
Formula-1
(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
(c) isolating (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide
(d) debenzylating (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide in presence of debenzylating agent, hydrogen source, SO3 complex, solvent
(e) isolating tributylammoniumsalt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide
(f) converting tributylammoniumsalt of 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
(g) isolating sodium [(2S,5R)-2-carbamoyl-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl] sulfate
2. The process as claimed in claim 1, wherein the coupling agent is selected from the group consisting of HOBt, pivaloyl chloride, EDC hydrochloride, dicyclohexylcarbodi imide.
3. The process as claimed in claim 1, wherein the base is selected from the group consisting of methylamine, dimethylamine, diethylamine,diisopropyl amine, diisopropylethylamine, diisobutylamine, triethyl amine, tributylamine,tert.butyl amine, pyridine, 4-di methyl ami nopyridine (DMAP), N-methyl morpholine (NMM),2,6-lutidine, lithium diisopropylamide (LDA), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-
diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole andthe like or mixture thereof.
4. The process as claimed in claim 1, wherein the debenzylating agent is selected from the . group consisting of 5% or 10% palladium on carbon, 20% palladium hydroxide on carbon,
*
platinum, rhodium, nickle.
5. The process as claimed in claim 1, wherein the SO3 complex is selected from the group consisting of sulphur trioxide complex, SO3 pyridine, SO3 dimethylformamide, SO3 triethylamine, SO3 trimethylamine, tributylsulfoammonium betaine, chlorosulfonic acid, oleum.
6. The process as claimed in claim 1, wherein the solvent MIBK, acetone, isopropyl acetate, ethyl acetate, dichloromethane, ethylene dichloride, methanol, ethanol, isopropanol, butanol, water and mixture thereof.
7. A process for preparing oftributylammoniumsalt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide of formula-4 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) isolating tributylammoniumsalt of trans-7-oxo-6-(sulphoxy)-l,6-diazabicyclo[3,2,l] octane-2-carboxamide
8. The process as claimed in claim 7, wherein the debenzylating agent is selected from the group consisting of 5% or 10% palladium on carbon, 20% palladium hydroxide on carbon, platinum, rhodium, nickle.
9. The process as claimed in claim 7, wherein the SO3 complex is selected from the group consisting of sulphur trioxide complex, SO3 pyridine, SO3 dimethylformamide, SCbtriethylamine, SO3 trimethylamine, tributylsulfoammonium betaine, chlorosulfonic acid,
oleum.
10. The process as claimed in claim 7, wherein the solvent is selected from the group consisting of MIBK, acetone, isopropyl acetate, ethyl acetate, dichloromethane, acetic acid or mixture
thereof.