DESC:Field of the invention:
The present invention relates to an improved process for the preparation of Relebactam monohydrate having chemical name [(2S,5R)-7-Oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl] hydrogen sulfate monohydrate of formula-1 which is represented by the following structural formula:

Background of the Invention:
Relebactam monohydrate (1) is a diazabicyclooctane beta-lactamase inhibitor, similar in structure to avibactam. Relebactam monohydrate (1) is a beta-lactamase inhibitor used to prevent hydrolysis of beta-lactam antibiotics, leading to increased effectiveness. As a beta-lactamase inhibitor, it blocks the ability of bacteria to break down a beta-lactam antibiotic. It is currently available in a combination product, which includes Imipenem and Cilastatin to treat complicated urinary tract infections (UTIs), pyelonephritis, and complicated intra-abdominal infections in adults. It is considered to be a last-line treatment option and gained FDA approval as part of the combination product Recarbrio in July 2019.

In the literature, Relebactam is prepared by debenzylation of compound of formula-(2) in the presence of Palladium on carbon, DABCO and Bis(trimethylsilyl)acetamide in isopropyl acetate followed by treatment of the filtered reaction mass with acetic acid and subsequent filtration of the resulting suspension to isolate N-Hydroxy compound of formula-(3). Later, the compound of formula-(3) is treated with triethylamine-sulfur trioxide complex to afford sulfonic acid derivative of compound of formula-(4), which upon further treatment with aq. potassium dihydrogen phosphate to transform into corresponding potassium salt of compound of formula-(5) in aqueous solution form. The aqueous solution of compound of formula-(5) is converted to corresponding tetrabutylammonium salt of formula-(6) by treatment with tetrabutylammonium hydrogen sulfate. The tetrabutylammonium salt of formula-(6) is further treated with trimethylsilyl bromide in acetonitrile followed by treatment with tetrabutylammonium acetate in acetic acid and further purification from aq. isopropanol to afford Relebactam monohydrate of formula-(1).

In general, literature process suffers from following disadvantages:
Debenzylation of compound-(2):
a) During debenzylation of compound-(2), several unidentified impurities are formed at varying higher hydrogen pressures and temperature, which is resulting in lower yield and less purity of Relebactam of formula-(1).
b) Protection of compound-(3) with (Bis(trimethylsilyl)acetamide (BSA), followed by deprotection under acidic conditions might lead to in-consistent purity of compound 3.

Sulfation of compound 3
During sulfation at higher temperatures, purity of compound 4 is inconsistent.

Boc-deprotection of 4
c) After deprotection, bromide content and several impurities were observed at higher level, which requires repeated purifications and thus resulting in lower yield of Relebactam.

In spite of having literature method for the preparation of Relebactam monohydrate of formula-1, there is still a need to develop, cost effective and commercially viable process for the preparation of Relebactam monohydrate of formula-1 on large scale operations.

The literature process needs to be improved for commercial manufacturing of Relebactam monohydrate of formula-1, due to above disadvantages. Hence, there is an urgent need for a simple, cost effective and commercially viable process for the preparation of compound of formula-1 on large scale.

Accordingly, the present process should be circumventing the following disadvantages like:
In hydrogenation of benzyl urea reaction:
a) Avoiding high hydrogen pressure (50 psi).
b) Controlling impurities formation by reducing the reaction temperature to <5 °C and hydrogen pressure (<10 psi).
c) Executing the debenzylation reaction in mixture of solvents in order to keep the formed product dissolved in the reaction mass. This allows the Pd/C to be filtered from the debenzylation reaction mass easily. Carrying out debenzylation reaction in a single solvent such as ethyl acetate might lead to the precipitation of formed product because of its poor solubility.
d) Avoiding concentration of solvent & isolation of hydroxy urea derivative after debenzylation and conducting sulfation reaction in-situ with TEA.SO3 complex without isolation of hydroxy urea. This requires the addition of TEA.SO3 complex to the reaction mass before debenzylation reaction begins. This allows the spontaneous sulfation of free hydroxyl obtained after debenzylation reaction.
e) Avoiding unnecessary usage of Bis(trimethylsilyl)acetamide (BSA) during debenzylation benzylurea.
In sulfation of hydroxy urea reaction:
f) Controlling impurities formation by reducing the reaction temperature to <5 °C.
In Boc deprotection step:
g) Avoiding usage of organic solvent like isopropyl alcohol for isolation of the product.
h) Analysing the quality of the isolated product using analytical techniques like HPLC and other methods.

Thus the present invention provides an efficient, economically viable, easily scalable process for the preparation of Relebactam monohydrate of formula-1 with high purity and overall yield.

Brief description of the present invention:
The first aspect of the present invention is to provide an improved process for the preparation of Relebactam monohydrate of formula-1 as depicted in scheme-1.

Scheme-1
Detailed description of the present invention:

The first aspect of the present invention is to provide an improved and commercially viable process for the preparation of Relebactam monohydrate of formula-1, comprising the following steps:
a) Debenzylation of compound 2 in the presence of palladium catalyst and organic base in an organic solvent/solvent mixture (to keep the debenzylated product dissolved in reaction mass) under hydrogen pressure under chilled conditions to get compound-3 followed by in-situ sulfation of compound-3 with TEA.SO3 complex in one pot followed by filtration of the catalyst to afford compound 4 present in filtrate,
b) reacting the reaction mass obtained after filtration in step-(a) in-situ with aqueous alkali metal phosphate to afford corresponding alkali metal salt of compound-5,
c) reacting the aqueous solution of step-(b) in-situ with alkylamine hydrogen sulfate salt followed by extraction with organic solvent and concentration to afford compound-6,
d) deprotection of Boc functional group in compound-6 with TMSBr or trifluoroacetic acid in an organic solvent to afford Relebactam of formula-1.
e) Relebactam is purified from aqueous organic solvents mixture to afford pharmaceutically pure Relebactam as monohydrate (formula-1).

Wherein,
In step-(a) of the present invention, the palladium catalyst used in debenzylation of benzyl urea of formula-2 is selected from 5-10% Palladium on carbon with (~50% wet) preferably ~10% Palladium on carbon (~50% wet) is selected for debenzylation.
In step-(a) of the present invention, the organic base is selected from trimethylamine, triethylamine, N,N-diisopropylethylamine, tributylamine or any other tertiary amine base.
In step-(a) of the present invention, the organic solvent or solvent mixture is selected from methanol, ethanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, n-butyl acetate, MDC, toluene, or any other suitable organic solvent or solvent mixture preferably ethyl acetate-methanol/ethanol/isopropyl alcohol.
In step-(a) of the present invention, the solvent ratio in organic solvent mixture varies from 0-100%.
In step-(a) of the present invention, debenzylation of benzyl urea conducted in the presence of hydrogen bubbling or under hydrogen pressure ranging from 0-30 psi pressure preferably below 10 psi.
In step-(a) of the present invention, debenzylation of benzyl urea conducted at temperature ranging from -5 to 20 °C preferably at -5 to 10 °C.
In step-(a) of the present invention, the Sulfur trioxide complex is selected from SO3-triethylamine complex, SO3-trimethylamine complex, SO3-DIPEA complex, SO3-DMF complex, SO3-dioxane complex, preferably SO3-triethylamine complex or any suitable SO3 complex.
In step-(a) of the present invention, sulfation is conducted at temperatures ranging from -5 to 25 °C preferably at -5 to 15 °C.
In step-(a) of the present invention, the reaction mass obtained after filtration was used in step-(b) without further isolation of formula-4.
In step-(a) of the present invention, alternatively, compound-3 obtained after debenzylation may be filtered at low temperature for the removal of palladium catalyst and the filtrate obtained at low temperature can be treated with TEA.SO3 Complex separately for effecting sulfation reaction to obtain compound-4.

In step-(b) of the present invention, the alkali metal phosphate is selected from anhydrous / hydrated salts like potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phophate, lithium dihydrogen phosphate and dilithium hydrogen phosphate or any other suitable alkali metal phosphates preferably sodium dihydrogen phosphate or potassium dihydrogen phosphate.

In step-(c) of the present invention, the aqueous layer containing potassium, lithium or sodium salt of compound of formula-5 is reacted with alkylamine hydrogen sulfate. The alkylamine hydrogen sulfate is selected from tetrabutylammonium hydrogen sulfate, cetyltrimethyl ammonium hydrogen sulfate, tetramethyl ammonium hydrogen sulfate hydrate, tetrahexylammonium hydrogensulfate or any other suitable alkylamine hydrogensulfate salt preferably tetrabutylammonium hydrogensulfate.
In step-(c) of the present invention, after completion of reaction, the product is extracted with organic solvent. The organic solvent is selected from methylene chloride, chloroform, ethylacetate, toluene, methyl tertiary butyl ether, isopropyl acetate, isopropyl ether, heptane, 2-methyltetrahydrofuran or any other suitable organic solvent preferably methylene chloride or chloroform.
In step-(c) of the present invention, the organic layer containing alkylamine sulfate salt is separated and concentrated to afford alkylamine sulfate salt of compound of formula-6 as foamy mass.

In step-(d) of the present invention, Boc deprotecting agent is selected from TMSBr or trifluoroacetic acid.
In step-(d) of the present invention, the organic solvent is selected from acetonitrile, methylene chloride, tetrahydrofuran.
In step-(d) of the present invention, Boc deprotection is conducted at temperature ranging from -5 to 35 °C preferably at 5-20 °C and treated with tetrabutyl ammonium acetate in acetic acid or sodium ethyl hexanoate to afford Relebactam.

In step-(e) of the present invention, Relebactam of formula-1 obtained in step-(e) is purified from organic solvent or aqueous organic solvent or solvent mixture. Organic solvent or aqueous organic solvent or solvent mixture is selected from acetonitrile, methanol, water, acetone, isopropyl alcohol, ethanol, tetrahydrofuran, 1,4-dioxane or any other suitable organic solvent.

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.

Examples:

Exampe-1: Preparation of Triethylamine-Sulphur trioxide Complex:

Chlorosulfonic acid (100.0 g, 1.0 eq.) dissolved in methylene chloride (300 mL, 3.0 V) was slowly added to the mixture of triethylamine (173.6 g, 2.0 eq.) and methylene chloride (600 mL, 6.0 V) at -5 to 5 °C under nitrogen atmosphere. The resulting reaction mass was stirred for 60-90 mins at 0-5 °C and quenched with cold water (500 mL, 5 V) at 10-15 °C and stirred the quenched reaction mass for 30 mins at 10-20 °C, separated the layers, washed the organic layer with DM water (500 mL, 5 V). Filtrate thus obtained was distilled off to get a residue which was subsequently added with n-Heptane (500 mL, 5.0 V) and cooled the resulting mass to 25-30 °C. Stirred the mass for 60 mins at the same temperature and filtered the solids, washed with n-heptane (100 mL, 1 V) to get the wet TEA-SO3 complex (140.2 g). Wet sample thus obtained was dissolved in methylene chloride (300 mL, 3 V) at 25-30 °C. The resulting solution was added with n-Heptane (900 mL, 9 V) at 25-30 °C. Precipitated out Triethylamine-Sulphur trioxide Complex was stirred at the same temperature for 2-3 h and filtered. Wet sample of Triethylamine-Sulphur trioxide Complex was dried to get pure crystalline Triethylamine-Sulphur trioxide Complex (118.5 g, 76.18% yield).

Exampe-2: Preparation of [(1R,2S,5R)-2-[(1-tert-butoxycarbonyl-4-piperidyl) carbamoyl]-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]sulfate, sodium salt (1:1) (Formula-5):
Formula-5 involves in-situ preparation of 4-[[[(1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl]amino]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (Formula-3)
And
[(1R,2S,5R)-2-[(1-tert-butoxycarbonyl-4-piperidyl)carbamoyl]-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl] sulfate, sodium salt (1:1) Formula-5)]:
The compound of Formula-2 (75.0 g, 1.0 mol. eq) was dissolved in a mixture of ethyl acetate (1350 mL, 18.0 V) and methanol (450 mL, 6.0 V) at room temperature and cooled to 0-5 °C in a 5.0 L hydrogenator kettle. The resulting solution was stirred for about 5 min and added sequentially 7.5 g of (10% w/w w.r.t formula-2) 10% Pd/C, triethylamine (152.2 g, 9.2 m.eq) and triethylamine-SO3 complex (195.3 g, 6.6 m.eq) at the same temperature. Subsequently, hydrogenator was evacuated with nitrogen gas (5 psi) twice followed by hydrogen gas twice (5 psi) as required. Subsequently, hydrogen gas was applied to the reaction mass at 0-5 °C at a pressure of 10±5 Psi. The reaction mass was maintained for 2 h at the same temperature and the progress of the reaction was monitored by HPLC for the contents of Formula-2 and Formula-3. After completion of the reaction, the reaction mass was filtered at 0-5 °C through hyflo bed under nitrogen atmosphere, washed the hyflo bed with pre-cooled (10 °C) ethyl acetate (250 mL, 3.3 V). To the filtrate, an aqueous solution of sodium dihydrogen phosphate (248.2 g, 11.0 m.eq) in DM water (4.87 L, 65 V) was added at below 15 °C and stirred at the same temperature for ~10 minutes. The reaction mass was warmed to 20-25 °C and maintained for 1 h. The aqueous layer was separated and extracted with ethyl acetate (375 mL, 5 V). The aqueous layer containing compound of formula-5 was used in the next stage without any further isolation.

Alternate procedure for the preparation of compound of formula-5 via the filtration of the reaction mass of compound of formula 3:
The compound of Formula-2 (20.0 g, 1.0 mol. eq) was added to the mixture of ethyl acetate (400 mL, 20.0 V) and methanol (132 mL, 6.6 V) at 25-30 °C. The resulting reaction mass was cooled to 0-5 °C and charged with triethylamine (0.29 g, 0.065 m.eq) and stirred for 5-10 minutes at the same temperature. The resulting reaction mass was transferred into a 2.0 L hydrogenator kettle and charged with 1.0 g of (5% w/w w.r.t Formula-2) 10% Pd/C. Subsequently, hydrogenator was evacuated with nitrogen gas twice followed by hydrogen gas twice as required. Subsequently, hydrogen gas was applied to the reaction mass at 0-5 °C at a pressure of 10±5 Psi. The reaction mass was maintained for 4 h at the same temperature and the progress of the reaction was monitored by HPLC for the contents of Formula-2 and Formula-3. After completion of the reaction, the reaction mass was filtered at 0-5 °C through hyflo bed under nitrogen atmosphere, washed the hyflo bed with pre-cooled (10 °C) ethyl acetate (80 mL, 4 V). Filtrate (650 mL) thus obtained was transferred into a 2.0 L RB flask and cooled to 0-5 °C. Subsequently, reaction mass was charged with triethylamine (40.69 g, 9.22 eq.) and TEA.SO3 complex (52.1 g, 6.6 eq.). The reaction mass was maintained for 4-5 h at the same temperature. After completion of the reaction, reaction mass was charged with sodium dihydrogen phosphate (66.2 g, 11.0 m. eq) dissolved in DM water (944 mL, 47.2 V) at below 15 °C and stirred at the same temperature for 10 minutes. The reaction mass was warmed to 20-25 °C and maintained for 1 h. The reaction mass was diluted with 350.0 mL of DM water and layers were separated. The Separated aqueous layer was washed with ethyl acetate (100 mL, 5 V). Separated aqueous layer (1400 mL) containing compound of formula-5 was taken to the next stage without any further isolation.
HPLC Purity of Aqueous layer containing compound of formula-5: 97.03%.

Exampe-3: Preparation of [(1R,2S,5R)-2-[(1-tert-butoxycarbonyl-4-piperidyl) carbamoyl]-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]sulfate, tetrabutylammonium salt (1:1) (Formula-6):
Aqueous layer (6.5 Lt) containing compound of formula-5 obtained in the above stage was transferred into RBF and treated with tetrabutylammonium hydrogensulfate (83.3 g, 1.5 m.eq) at 20-25 °C for 1 h. Following the completion of maintenance, charged methylene chloride (750 mL, 10 V) into the reaction mass and extracted compound of Formula-6 for 20-25 minutes at 20-25 °C. Separated aqueous layer was re-extracted with methylene chloride (750 mL, 10 V) at the same temperature. Separated MDC layer was washed thrice with (3×1500 mL) of DM water. MDC layer was dried over sodium sulfate (150 g, 2.0 W) and distilled at below 30 °C. The resultant foamy mass was co-distilled with acetonitrile (3×225 mL). Foamy mass (115 g) (compound of formula-6) thus obtained was dissolved in (225 mL, 3 V) of acetonitrile and carried to next stage. HPLC Purity: 96.50%.

Exampe-4: Preparation of (1R,2S,5R)-7-oxo-2-(piperidin-1-ium-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate hydrate (compound of formula-1):
The acetonitrile solution containing compound of formula-6 thus obtained in the above stage was further diluted with (900 mL, 12 V) of acetonitrile at 25-30 °C and cooled to 5-10 °C. Bromotrimethylsilane (37.6 g, 1.5 m. eq) was charged to the above solution and warmed the reaction mass to 20±2 °C. Reaction mass was maintained for 10-16 h at the same temperature and cooled to 0-5 °C. After completion of the reaction by in-process HPLC, tetrabutylammonium acetate in acetic acid (23.68 g, 0.4 m. eq) dissolved in mixture of water and acetonitrile (64 mL/56 mL, 0.85 V/0.7 V) was charged to the reaction mass at once, cooled the reaction mass to 0±2 °C and maintained for 6 h. The precipitate of compound of formula-1 was filtered, washed with acetonitrile (225 mL, 3 V) and dried to get 48.33 g (80.65%) of Relebactam (Non-Sterile). HPLC Purity: 99.15%.

Exampe-5: (1R,2S,5R)-7-oxo-2-(piperidin-1-ium-4-ylcarbamoyl)-1,6-diazabicyclo [3.2.1]octan-6-yl sulfate hydrate (1:1) (Formula-1):
Compound of formula-1 (non-sterile) (100.0 g) was dissolved in 1:2 pre-mixture of Acetonitrile and DM Water (Prepared by mixing 200 mL of Acetonitrile and 400 mL of DM Water) under stirring at 30-35 °C for 10-15 min. The clear solution thus obtained was charged with activated carbon (10.0 g) and stirred for 20 mins at the same temperature and filtered through hyflo, washed the bed with 100 mL of 1:2 mixture of Acetonitrile and DM Water mixture (Prepared by mixing 33.3 mL of Acetonitrile and 66.6 mL of DM water). Subsequently, the collected filtrate was passed through 0.4 micron filter paper and cooled the filtrate thus obtained to 0-5 °C. Charged pre-filtered (through 0.4 micron filter paper) methanol (40 V) slowly and stirred the resulting precipitate for 4-5 h at the same temperature. Following the completion of maintenance, the precipitated out solids were filtered, washed with pre-filtered methanol (2 V) and dried under suction for 15-20 min. Wet Relebactam thus obtained was unloaded and dried under vacuum (200 mbar) at 25-30 °C for 3-4 h to get 82.31 g of Relebactam sterile (Formula-1) (82.31% yield). HPLC Purity: 99.78%.
,CLAIMS:We Claim:

1. An improved and commercially viable process for the preparation of Relebactam monohydrate of formula-1, comprising the following steps of:
a) i) Debenzylation of compound 2 in the presence of palladium catalyst along with
organic base in an organic solvent / solvent mixture under hydrogen pressure to
afford compound-3 followed by in-situ sulfation of compound-3 with TEA.SO3
complex and filtration of the catalyst to afford compound 4 in filtrate, (OR)
ii) reacting compound 3 obtained after filtration of debenzylation reaction mass in-
situ with sulfur trioxide complex in the presence of organic base such as
triethylamine to afford Boc sulfate of compound-4 in-situ,
b) reacting the step-(a) reaction mass in-situ with aqueous alkali metal phosphate other than potassium dihydrogen phosphate to afford corresponding alkali metal salt of compound-5 in-situ,
c) reacting aqueous solution of step-(b) in-situ with tetrabutylammonium hydrogen sulfate followed by extraction with organic solvent and concentration to afford compound-6 in-situ,
d) deprotection of Boc functional group of compound-6 with TMSBr or trifluoroacetic acid in an organic solvent to afford Relebactam of formula-1.
e) Relebactam is purified from aqueous organic solvents mixture to afford pharmaceutically pure Relebactam as monohydrate (formula-1).

2. The process as claimed in claim-1, wherein,
In step-(a) the palladium catalyst used in debenzylation of benzyl urea of formula-2 is
selected from 5-10% Palladium on carbon with (~50% wet) preferably ~10% Palladium on carbon (~50% wet) is selected for debenzylation.
In step-(a) the organic base is selected from trimethylamine, triethylamine, N,N-
diisopropylethylamine, tributylamine or any tertiary amine base.
In step-(a) the organic solvent or solvent mixture is selected from methanol, ethanol,
isopropyl alcohol, ethyl acetate, isopropyl acetate, n-butyl acetate, MDC, toluene, or any other suitable organic solvent or solvent mixture preferably ethyl acetate and methanol.

3. The process as claimed in claim-1, wherein,
In step-(a) debenzylation of benzyl urea conducted in the presence of hydrogen
bubbling or under hydrogen pressure ranging from 0-30 psi pressure preferably below 10 psi.

4. The process as claimed in claim-1, wherein,
In step-(a) the debenzylation of benzyl urea conducted at temperature ranging from -5
to 20 °C preferably at -5 to 10 °C.

5. The process as claimed in claim-1, wherein,
In step-(a) the sulfation is conducted at temperature ranging from -5 to 25 °C preferably
at -5 to 15 °C.

6. The process as claimed in claim-1, wherein,
In step-(b) the alkali metal phosphate is selected from anhydrous / hydrated salts like
sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phophate, lithium dihydrogen phosphate and dilithium hydrogen phosphate or any other suitable alkali metal phosphates preferably sodium dihydrogen phosphate.

7. An improved and commercially viable process for the preparation of Relebactam monohydrate of formula-1, comprising the following steps of:
a) i) Debenzylation of compound 2 in the presence of palladium catalyst along with
triethylamine in a mixture of ethyl acetate and methanol under hydrogen pressure
under chilled conditions to afford compound-3 followed by in-situ sulfation of
compound-3 with SO3-triethylamine complex and filtration of the catalyst to
afford compound 4 in filtrate, (OR)
ii) alternatively, reacting compound 3 obtained after filtration of debenzylation
reaction mass in-situ with SO3-triethylamine complex in the presence of
triethylamine under chilled conditions to afford Boc sulfate of compound-4 in-
situ,
b) reacting the step-a reaction mass in-situ with aqueous sodium dihydrogen phosphate to afford sodium salt of compound-5 in-situ,
c) reacting aqueous solution of step-b in-situ with tetrabutylammonium hydrogen sulfate followed by extraction with MDC and concentration to afford compound-6 in-situ,
d) deprotection of Boc functional group of compound-6 with TMSBr in acetonitrile to afford Relebactam of formula-1.
e) Relebactam obtained in step-d is purified from aqueous acetonitrile and methanol to afford pharmaceutically pure Relebactam as monohydrate (formula-1).

8. The process as claimed in claim-1 or 7, the obtained Relebactam monohydrate having purity more than 99.75% by HPLC.