DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Avibactam and its pharmaceutically acceptable salts thereof. Specifically, the present invention discloses a process for the preparation of Avibactam sodium of Formula I using novel intermediate of Formula V. More preferably, the present invention relates to a process for the preparation of intermediate of Formula V and its use for the preparation of Avibactam of Formula III and Avibactam sodium of Formula I.


BACKGROUND OF THE INVENTION

Avibactam is a non-ß-lactam ß-lactamase inhibitor which is available in market in combination with ceftazidime used in complicated urinary tract infections (cUTIs) [including pyelonephritis], complicated intra-abdominal infections (cIAIs), hospital-acquired pneumonia (HAP) [including ventilator-associated pneumonia (VAP)], and other infections caused by aerobic Gram-negative organisms in patients with limited treatment options.

The synthesis of Avibactam sodium is reported in WO02/10172A1 discloses the synthetic route (scheme-A) for Avibactam sodium where it uses Dowex resin in the final stage. However, this process doesn’t disclose about enantiomeric purity of neither intermediates nor final product.
Scheme-A

WO2012/172368 and US8,288,553 disclosed the synthetic route which successfully avoided resin stage instead uses sodium-ethyl-2-heaxanoate salt as sodium source (Scheme-B). This route also avoided the key piperidine starting material and used gamma lactam instead. This route forms mixture of cis-trans intermediate which is further processed to get enantiaomerically pure API. Selective hydrolysis of cis-trans mixture is achieved by lithium hydroxide hydrolysis followed by treatment with pivaloyl chloride.
Scheme-B

Both scheme-A and Scheme-B are used Avibactam tetrabutyl ammonium salt as N-1 stage where the purity of N-1 stage is controlling the API purity. Mentioned intermediates also must be handled under controlled atmosphere in order to avoid degradation and impurity formation. Overall yield is very less. These process experience operational difficulty at industrial scale and degradation of products due to harsh reaction conditions limiting the commercial production.

CN111777607 discloses the new process (Scheme C) for the synthesis of Avibactam sodium through novel intermediate where ester intermediate is hydrolysed then converted to amide. This process increase the isolation stage and stability of the acid intermediate is not provided. This process also not significantly discussed about scale up possibility.
Scheme-C

The prior art involves isolation of intermediate IV leading to an increase in the manufacturing cycle time, less yield and hence not suitable for commercial-scale manufacturing. In spite of progress made compared to the original processes, there is still a need for manufacturing Avibactam sodium, via simple, cost effective and industrially viable process.

With our continued search and intense investigation, we finally achieved a process for the preparation Avibactam sodium via novel intermediate, which overcomes all difficulties in prior art and makes the process industrially viable and yield the Avibactam sodium in better quality.

OBJECT OF THE INVENTION

The principal object of the present invention is to overcome or alleviate at least one of the deficiencies of prior art and provide a useful alternative for the preparation of Avibactam sodium which is suitable for human consumption.
According to one object of the present invention, there is provided a process for the preparation of Avibactam and pharmaceutically acceptable salts thereof, specifically Avibactam sodium.
It is another object of the present invention to provide Avibactam sodium using novel intermediate of Formula V.

It is another object of the present invention to provide a simple, economic and industrially viable process for the preparation of Avibactam and its salts specifically Avibactam sodium.

It is yet another object of the present invention to provide a process for the preparation of novel intermediate of Formula V.

It is yet another object of the present invention to provide a process for the preparation of Avibactam sodium which is carefully designed to improve stability and to design overall process at much scalable conditions.

It is yet another object of the present invention, there is provided a simple, commercially viable, economical and environment friendly process for preparing Avibactam sodium in high yield with high purity using novel intermediate of Formula V.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided an improved process for the preparation of Avibactam and pharmaceutically acceptable salts thereof.

In accordance with the present invention, there is provided a process for the preparation of Avibactam sodium, the process comprising using novel intermediate of Formula V.

In accordance with the present invention, there is provided novel intermediate of Formula V.

In accordance with the present invention, there is provided a process for the preparation of the intermediate of Formula V and its use for the preparation of Avibactam of Formula III and Avibactam sodium of Formula I.

According to one aspect of the present invention there is provided an efficient and cost effective process for the preparation of Avibactam sodium of Formula I, as shown in scheme-1.

According to another aspect of the present invention there is provided an efficient process for the preparation of Avibactam sodium of Formula I, as shown in scheme-2.

According to yet another aspect of the present invention there is provided an efficient process for the preparation of Avibactam sodium of Formula I, as shown in scheme-3.

DETAIL DESCRIPTION OF THE INVENTION

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

The present invention relates to a process for the preparation of Avibactam of Formula III or Avibactam sodium of Formula I

comprising the steps of:
(i) converting compound of Formula VI to compound of Formula V;

wherein R1 is C1-C5 alkyl;
(ii) converting compound of Formula V to Avibactam of Formula III; and
(iii) optionally converting Avibactam of Formula III to Avibactam sodium of Formula I.

Step (i) comprises debenzylation and sulfonation which is carried out in presence of solvent, base and sulfonating reagent.
Solvent for step (i) is selected from the group comprising of alcohol, ethers MDC, DMF, DMSO, water or mixture thereof. Alcohol is selected from the group comprising of C1-C4 alcohol such as methanol, ethanol, propanol, isopropanol, butanol and the like. Ether is selected from the group comprising of MTBE, THF, 2-methyl THF, dioxane.
Base for step (i) is selected from the group comprising of methylamine, diethylamine, triethylamine, di-isopropylethylamine, pyridine Na2CO3, NaHCO3, K2CO3, KH2PO4, sodium acetate and the like.
Sulfonating reagent for step (i) is selected from the group comprising of SO3 complex with amines (TMA, TEA, Pyridine, dimethyl aniline), DMF, DMAC and Poly vinyl pyridine; chloro sulfonic acid, sulfamic acid of SO3-TMA, SO3-TEA, SO3-pyridine and the like.
Temperature for step (i) is from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC.

Step (ii) comprises -
(a) direct conversion (amidation step); or
(b) with or without isolation of salt of Formula IV (salt formation and amidation step).

Wherein Salt in Formula IV is selected from amine salts and metal salts selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt and the like.
Step (ii) is carried out in presence of solvent and base.
Solvent in step (ii) is selected from the group comprising of C1-C4 alcohol, ethers (THF, 2methyl-THF, dioxane), toluene, xylene and water and the like and mixture thereof.
Base for step (ii) is ammonia source selected from the group comprising of Ammonia gas, Ammonium hydroxide, ammonia solution in alcohol or ammonia solution in ethers and the like.
Temperature for step (ii) is from about 20oC to about 40oC, preferably about 20oC-35oC and most preferably about 20oC-25oC.

Step (iii) comprises following process:
(a) direct conversion; or
(b) with or without isolation of intermediate salt compound of Formula II.

wherein salt in Formula II is selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt and the like.

In an embodiment, the present invention relates to a process for the preparation of compound of Formula V or its salt of Formula IV

wherein R1 is C1-C5 alkyl; and
Salt in Formula IV is selected from amine salts and metal salts selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt and the like.
comprising the steps of:
(i) converting compound of Formula VI to compound of Formula V; and

(ii) optionally converting compound of Formula V to its salt of Formula IV.
Step (i) comprises debenzylation and sulfonation which is carried out in presence of solvent, base and sulfonating reagent.
Solvent for step (i) is selected from the group comprising of alcohol, ethers MDC, DMF, DMSO, water or mixture thereof. Alcohol is selected from the group comprising of C1-C4 alcohol such as methanol, ethanol, propanol, isopropanol, butanol and the like. Ether is selected from the group comprising of MTBE, THF, 2-methyl THF, dioxane.
Base for step (i) is selected from the group comprising of methylamine, diethylamine, triethylamine, di-isopropylethylamine, pyridine Na2CO3, NaHCO3, K2CO3, KH2PO4, sodium acetate and the like.
Sulfonating reagent for step (i) is selected from the group comprising of SO3 complex with amines (TMA, TEA, Pyridine, dimethyl aniline), DMF, DMAC and Poly vinyl pyridine, chloro sulfonic acid, sulfamic acid of SO3-TMA, SO3-TEA, SO3-pyridine and the like.
Temperature for step (i) is from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC.

In an embodiment, the present invention relates to a process for the preparation of compound of Formula V or its salt of Formula IV

wherein R1 is C1-C5 alkyl; and
Wherein Salt in Formula IV is selected from amine salts and metal salts selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt and the like.
comprising the steps of:
(i) converting compound of Formula X or its salt of Formula IX to compound of Formula VI;

wherein R1 is C1-C5 alkyl; and
salt in Formula IX is selected from the group comprising of oxalate, citrate, tartrate, acetate, sulfate, hydrochloride, p-toluene sulfonate and the like;
(ii) converting compound of Formula VI to compound of Formula V;

(iii) optionally converting compound of Formula V to its salt of Formula IV.
Step (i) comprises reaction to be carried out in presence of solvent, base and reagent.
Solvent for step (i) is selected from the group comprising of dichloromethane (DCM), chloroform, carbon tetrachloride, ethyl acetate, THF, 2-methyl THF, 1,4-dioxane, chlorobenzene, toluene, xylene and the like and mixture thereof.
Base for step (i) is organic amine selected from the group comprising of methylamine, diethylamine, triethylamine, di-isopropylethylamine, pyridine and the like.
Reagent for step (i) is selected from the group comprising of CDI (N.N’-Carbonyldiimidazole), Phosgene, diphosgene, triphosgene and the like.
Temperature for step (i) is from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC.

In an embodiment, the present invention relates to a process for the preparation of compound of Formula V or its salt of Formula IV

wherein R1 is C1-C5 alkyl; and
salt in Formula IV is selected from amine salts and metal salts selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt and the like;
comprising the steps of:
(i) converting compound of Formula X or its salt of Formula IX to compound of Formula VIII;

wherein R1 is C1-C5 alkyl;
salt in Formula IX is selected from the group comprising of oxalate, citrate, tartrate, acetate, sulfate, hydrochloride, p-toluene sulfonate and the like;
R2 is selected from the group comprising of Bz, CBz, Fmoc, BOC, COCF3, C(Ph)3 and the like;
(ii) optionally converting compound of Formula VIII to salt of Formula VII;

Wherein HX in Formula VII is selected from the group comprising of HCl, H2SO4, H3PO4, HNO3 AcOH, p-Toluenesulfonic acid and the like;
(iii) converting compound of Formula VIII or salt of Formula VII to compound of Formula VI;

(iv) converting compound of Formula VI to compound of Formula V;
(v) optionally converting compound of Formula V to its salt of Formula IV.

Step (i) comprises N-Protection reaction to be carried out in presence of solvent, base and reagent.
Solvent for step (i) is selected from the group comprising of dichloromethane (DCM), chloroform, carbon tetrachloride, toluene, ethyl acetate, THF, 1,4-dioxane, chlorobenzene and the like and mixture thereof.
Base for step (i) is selected from the group comprising of methylamine, diethylamine, triethylamine, di-isopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate and the like.
Reagent for step (i) is selected from the group comprising of Reagent: Bz-Cl, CBz-Cl, Fmoc-Cl, BOC anhydride, Trifluoro acetic anhydride, trityl chloride and the like;
Temperature for step (i) is from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC.

Step (ii) comprises salt formation reaction to be carried out in presence of solvent and acid.
Solvent for step (ii) is selected from the group comprising of alcohol, ketone, ester, ether, water or mixture thereof, Solvent is preferably selected from methanol, ethanol, propanol, isopropanol, Butanol, ethyl acetate, THF, 1,4-dioxane, methyl t-butyl ether, acetone, 2-butanone and the like, water and mixture thereof.
Acid for step (ii) is selected from the group comprising of Hydrochloric acid, Sulfuric acid, Nitric acid, Phosphoric acid, Acetic acid, Trifluoro acetic acid (TFA), p-toulene sulfonic acid (PTSA) and the like.

Step (iii) comprises reaction to be carried out in presence of solvent, base and reagent.
Solvent for step (iii) is selected from the group comprising of dichloromethane (DCM), chloroform, carbon tetrachloride, toluene, ethyl acetate, THF, 1,4-dioxane, chlorobenzene, acetonitrile and the like and mixture thereof.
Base for step (iii) is selected from the group comprising of methylamine, diethylamine, triethylamine, di-isopropylethylamine, pyridine, piperidine, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate and the like.
Reagent for step (iii) is selected from the group comprising of Reagent: CDI (N,N’-Carbonyldiimidazole) and the like;
Temperature for step (iii) is from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC.

In an embodiment, the present invention relates to a process for the preparation of Avibactam of Formula III or Avibactam sodium of Formula I

comprising the steps of:
(i) converting compound of Formula X or its salt of Formula IX to compound of Formula VI;

wherein R1 is C1-C5 alkyl; and
salt in Formula IX is selected from the group comprising of oxalate, citrate, tartrate, acetate, sulfate, hydrochloride, p-toluene sulfonate and the like;
(ii) converting compound of Formula VI to compound of Formula V;

(iii) optionally converting compound of Formula V to its salt of Formula IV;

Wherein salt in Formula IV is selected from amine salts and metal salts selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt and the like;
(iv) converting compound of Formula V or salt of Formula IV to Avibactam of Formula III; and
(iv) optionally converting Avibactam of Formula III to Avibactam sodium of Formula I.

Step (i) comprises
(a) direct conversion; or
(b) with or without isolation of intermediate compound of Formulae VIII and VII.

wherein HX in Formula VII is selected from the group comprising of HCl, H2SO4, H3PO4, HNO3 AcOH, p-Toluenesulfonic acid.

In an embodiment, the present invention relates to a process for the preparation of Avibactam of Formula III or Avibactam sodium of Formula I

comprising the steps of:
(i) converting compound of Formula X or its salt of Formula IX to compound of Formula VIII;

wherein R1 is C1-C5 alkyl;
salt in Formula IX is selected from the group comprising of oxalate, citrate, tartrate, acetate, sulfate, hydrochloride, p-toluene sulfonate and the like;
R2 is selected from the group comprising of Bz, CBz, Fmoc, BOC, COCF3, C(Ph)3 and the like;
(ii) optionally converting compound of Formula VIII to salt of Formula VII;

Wherein HX in Formula VII is selected from the group comprising of HCl, H2SO4, H3PO4, HNO3 AcOH, p-Toluenesulfonic acid and the like;
(iii) converting compound of Formula VIII or salt of Formula VII to compound of Formula VI;

(iv) converting compound of Formula VI to compound of Formula V;

(v) optionally converting compound of Formula V to its salt of Formula IV;

Wherein salt in Formula IV is selected from amine salts and metal salts selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt and the like;
(vi) converting compound of Formula V or salt of Formula IV to Avibactam of Formula III; and
(vii) optionally converting Avibactam of Formula III to Avibactam sodium of Formula I.

In an embodiment, the present invention relates to a process for the preparation of Avibactam of Formula III or Avibactam sodium of Formula I

comprising the steps of:
(i) converting compound of Formula VI’ to compound of Formula V’;

(ii) converting compound of Formula V’ to Avibactam of Formula III; and
(iii) optionally converting Avibactam of Formula III to Avibactam sodium of Formula I.

Step (i) comprises debenzylation and sulfonation which is carried out in presence of solvent, base and sulfonating reagent.
Solvent for step (i) is selected from the group comprising of alcohol, water or mixture thereof. Alcohol is selected from the group comprising of C1-C4 alcohol such as methanol, ethanol, propanol, isopropanol, butanol and the like.
Base for step (i) is organic amine selected from the group comprising of methylamine, diethylamine, triethylamine, di-isopropylethylamine, pyridine and the like.
Sulfonating reagent for step (i) is selected from the group comprising of SO3 complex with amines (TMA, TEA, Pyridine, dimethyl aniline), DMF, DMAC and Poly vinyl pyridine, chloro sulfonic acid, sulfamic acid of SO3-TMA, SO3-TEA, SO3-pyridine and the like.
Temperature for step (i) is from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC.

Step (ii) comprises -
(a) direct conversion (amidation step); or
(b) with or without isolation of salt of Formula IV (salt formation and amidation step).

wherein Salt in Formula IV is selected from amine salts and metal salts selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt and the likeStep (ii) is carried out in presence of solvent and base.
Solvent in step (ii) is alcohol selected from the group comprising of C1-C4 alcohol such as methanol, ethanol, propanol, isopropanol, butanol and the like and mixture thereof.
Base for step (ii) is ammonia source selected from the group comprising of Ammonia gas, Ammonium hydroixide, methanolic ammonia and the like.
Temperature for step (ii) is from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC.

In an embodiment, the present invention relates to a process for the preparation of compound of Formula V’ or its salt of Formula IV’

comprising the steps of:
(i) converting compound of Formula VI’ to compound of Formula V’; and

(ii) optionally converting compound of Formula V’ to its salt of Formula IV’.

In an embodiment, the present invention relates to a process for the preparation of Avibactam of Formula III or Avibactam sodium of Formula I

comprising the steps of:
(i) converting compound of Formula X’ or its salt of Formula IX’ to compound of Formula VI’;

wherein salt in Formula IX’ is selected from the group comprising of oxalate, citrate, tartrate, acetate, sulfate, hydrochloride, p-toluene sulfonate and the like;
(ii) converting compound of Formula VI’ to compound of Formula V’;

(iii) converting compound of Formula V’ to Avibactam of Formula III; and
(iv) optionally converting Avibactam of Formula III to Avibactam sodium of Formula I.

Step (i) comprises following process:
(a) direct conversion; or
(b) with or without isolation of intermediate compound of Formulae VIII’ and VII’ or

wherein HX in Formula VII’ is selected from the group comprising of HCl, H2SO4, H3PO4, HNO3 AcOH, p-Toluenesulfonic acid and the like;
(c) with or without isolation of intermediate compound of Formulae VIII’’ and VII’’

wherein HX in Formula VII’’ is selected from the group comprising of HCl, H2SO4, H3PO4, HNO3 AcOH, p-Toluenesulfonic acid and the like;

Avibactam Sodium of Formula I is prepared from Avibactam of Formula III according to the known methods of prior art.

The problem has been solved by inventors by providing an improved process for the preparation of Avibactam or its salt by using novel intermediate of Formula V. Using stable intermediate of Formula V allows industrially viable process for the preparation of Avibactam sodium. Intermediate of Formula V plays a vital role in achieving Avibactam sodium with better yield and high purity.

ADVANTAGES OF THE INVENTION
Compared with prior art, the beneficial effects of the present invention are:
1. Process of the instant invention results in novel intermediate of Formula V.
2. As per process of instant invention intermediate of Formula V is highly stable and handling at industrial scale would be much easier.
3. Moreover, sulphate group in novel intermediate of Formula V eventually stabilizes the compound and further conversion steps can be carried out under ambient conditions without much product degradation.
4. Purity and yield of Avibactam sodium prepared according to process of instant invention is high as compare to prior art.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail and are not intended and should not be interpreted as a limitation thereon. Those skilled in the art can select any appropriate reaction condition and within scope of the present invention.

EXAMPLES
Example 1: Preparation of compound of Formula-VIII’ (Fmoc protection)
10g of ethyl (2S,5R)-5-((benzyloxy)amino piperidine-2-carboxylate oxalate (Formula IX’) was added to 70 ml of ethyl acetate at 20-30°C and cooled to 10-15°C. Slowly added 8.7g of N, N-diisopropyl ethylamine at 10-15°C in 10-30 min. Then, 7.0 g of Fmoc chloride was dissolved in 20 ml of methylene chloride and added to the reaction mass. The reaction mass was heated to 35-45°C and stirred. Then reaction mass was cooled to 20-30°C and filtered. Filtrate was washed twice with DI water (2x40 ml) and the organic layer was evaporated to obtain crude product as thick oil to semisolid.
Yield: 13.0g (98% w/w); HPLC purity: 98.85%
Example 2: Preparation of compound of Formula-VII’ (hydrochloride Salt)
13.0g of compound of Formula-VIII’ was dissolved in 25 ml of Acetone and 30 ml of DI water was added to it. Then 3N hydrochloric acid (25ml) was slowly added to the reaction mass at 20-30°C. Reaction mas was stirred for 2-3 hours and filtered. Wet cake was washed with DI water (10 ml) and dried in a vacuum oven at 40-45°C to afford product (hydrochloride salt) as a white to off-white solid.
Yield: 13.8 g (97% w/w); HPLC purity: 98.63%
Example 3: Preparation of compound of Formula-VII’ (Sulfate Salt)
13g of compound of Formula-VIII’ was dissolved in 25 ml of Acetone and 30 ml of DI water was added to it. Then 1N Sulfuric acid (20 ml) was slowly added to the reaction mass. Reaction mass was stirred for 2-3 hours and then filtered. Wet cake was washed with DI water (10 ml) and dried in a vacuum oven at 40-45°C to afford product as a white to off-white solid.
Yield: 13.0 g (90% w/w); HPLC purity: 98.23%

Example 4: Preparation of compound of Formula-VIII’’ (BOC protection)
50g of ethyl (2S,5R)-5-((benzyloxy)amino piperidine-2-carboxylate oxalate (Formula IX’) was added to 300 ml of methylene dichloride at 20-30°C the cooled 0-5°C. 44.3 g of Boc anhydride was added to it. Then, 43.7 g of DIPEA was slowly added for 60-90 min at 0-5°C. Raised the reaction mass temperature to 20-30°C and stirred. Reaction mass was washed with DI water and the organic layer was distilled to afford crude product. 300 ml of Hexanes was added to crude, stirred for 2-3 hours at 20-30°C and filtered. Wet cake was washed with Hexanes (50 ml) and dried under vacuum at 40-45°C to afford product as white to off-white solid.
Yield: 48.2g (98% w/w); HPLC purity: 99.66%
Example 5 Preparation of compound of Formula-VII’’ (acetate salt)
20 ml of Toluene was added to 10 g of compound of Formula-VIII’’ and cooled to 0-5°C. Acetic acid (1.9 g) was dissolved in 10 ml of Toluene and slowly added to the reaction mass and stirred at 0-5°C. Toluene was distilled. Residue was added with 80 ml of hexanes. The reaction mass was stirred for 1 hour at 10-15°C and filtered. The wet cake was washed with Hexane and dried under vacuum at 40-45°C to afford product as white to pale brown solid.
Yield: 9.3 g (80% w/w); HPLC purity: 98.77%
Example 6: Preparation of compound of Formula-VI’
70 ml of methylene dichloride was added to 10g of compound of Formula-X’ and cooled to 0-5°C. CDI (8.7 g) was added slowly to reaction mass and temperature raised to 20-30°C. Slowly added DIPEA (9.2 g) to it and stirred. Reaction mass was washed with DI water (50 ml) followed by aqueous oxalic acid (50 ml). The organic layer was separated and distilled to afford oily to semisolid crude product. Then 30 ml of acetone was added to it and stirred at 25-30°C. Then reaction mass was cooled to 0-5°C and added DI water (40 ml). The reaction mass was stirred for 1 hour at 0-5°C and filtered. Wet cake was washed with DI water (10 ml) and dried under vacuum at 40-45°C to afford product as white to off-white solid.
Yield: 6.8 g (68% w/w); HPLC purity: 99.59%
1H NMR (CDCl3, 400 MHz, dppm): 1.27-1.31 (t, 3H), 1.65-1.71 (m, 1H), 2.01-2.12 (m, 3H), 2.91-2.94 (d, 1H), 3.04-3.07 (broad d, 1H), 3.32 (broad, 1H), 4.08-4.10 (broad t, 1H), 4.21-4.26 (q, 2H), 4.89-4.91 (d, 1H), 5.07-5.04 (d, 1H), 7.27-7.43 (m, 5H);
13C NMR (CDCl3, 400 MHz, dppm): 14.97, 20.75, 21.99, 48.25, 59.07, 60.51, 62.46, 79.07, 129.34, 129.53, 130.06, 136.55, 168.97, 171.62; m/z 263.90 (M-H);
FTIR (cm-1): 3444.3, 3063.4, 3026.6, 2980.7, 2960.5, 1728.0, 1607.4, 1498.0, 1470.9, 1454.3, 1376.9, 1321.4, 1254.4, 1195.8, 1143.8, 1091.5, 1069.6, 1018.7, 979.6, 920.1, 891.4, 865.6, 803.1, 783.2, 739.6, 699.0, 640.8; m/z: 305.10 (M+H).
Example 7: Preparation of compound of Formula-VI’
100 ml of methylene dichloride was added to 10 g of compound of Formula-X’ and cooled to 0-5°C. Added Fmoc chloride (9.2 g) and DIPEA (5.0 g) to it. Raised the reaction temperature to 20-30°C and stirred. CDI (11.2 g) was added slowly to reaction mass and stirred at 20-30°C. Slowly added diethylamine (6.5 g) to the reaction mass and stirred. The reaction mass was washed with 150 ml of DI water followed by 10% w/w aqueous oxalic acid (150 ml). The organic layer was separated and distilled to afford oily to semisolid crude product. Then 60 ml of acetone was added to it and stirred. Reaction mass was cooled to 0-5°C and added DI water (90 ml). The reaction mass was stirred for 1 hour at 0-5°C and filtered. Wet cake was washed with DI water and dried under vacuum at 40-45°C to afford product (white to off-white solid).
Yield: 8.2 g (82% w/w); HPLC purity: 99.61%
Example 8: Preparation of compound of Formula-VI’
100 ml of Toluene was added to 10g of compound of Formula-X’ at 20-30°C. Boc anhydride (9.4 g) and triethylamine (4.3 g) were added to the reaction mass under inert atmosphere at 20-30°C then stirred. Cooled to 0-5°C. 8.7 g of CDI was added followed by addition of 5.4 g of triethylamine to reaction mass. Raised reaction mass temperature to 40-45°C and stirred. The reaction mass was cooled to 0-5°C and 22.1g of methane sulfonic acid was added to it. Raised the reaction temperature to 25-35°C and stirred. Then added aqueous potassium carbonate solution (20 ml) to the reaction mass and stirred for 30-60 minutes before layers were separated. The organic layer was washed with aqueous oxalic acid solution and DI water. The organic layer was separated and distilled to afford crude product. Then 20 ml of acetone was added to it at 25-30°C and stirred. Reaction mass was cooled to 0-5°C and added DI water (30 ml). The reaction mass was stirred for 1 hour at 0-5°C and filtered. Wet cake was washed with DI water and dried under vacuum at 40-45°C to afford product as white to off-white solid.
Yield: 8.6 g (86% w/w); HPLC purity: 99.57%
Example 9: Preparation of compound of Formula-VI’
100 ml of 2-methyl tetrahydrofuran was added to 10 g of compound of Formula-X’ under inert atmosphere and cooled to 0-5°C. 3.7 g of triphosgene was dissolved in 50 ml of 2-methyl tetrahydrofuran and added slowly to reaction mass. Slowly added triethylamine (5.2 ml). Stirred the reaction at 0-5°C. The reaction mass was quenched with aqueous sodium bicarbonate solution. The reaction mass was washed with 50 ml of DI water followed by aqueous oxalic acid (50 ml). The organic layer was separated and distilled to afford oily to semisolid crude product. Then 30ml of acetone was added to it at 25-30°C and stirred. Reaction mass was cooled to 0-5°C and added DI water (30 ml). The reaction mass was stirred for 1 hour at 0-5°C and filtered. The wet cake was washed with 10 ml of DI water and dried under vacuum at 40-45°C to afford product as white to off-white solid.
Yield: 8.9 g (89% w/w); HPLC purity: 99.28%
Example 10: Preparation of compound of Formula-VI’
70 ml of methylene dichloride was added to 10g of compound of Formula-VII’ (hydrochloride salt) and cooled to 0-5°C. 4.85g of CDI was added slowly to reaction mass. Raised reaction mass temperature to 20-30°C and slowly added DIPEA (3.8g). Stirred the reaction at 20-30°C and then 1.46g of diethylamine was added to it. The reaction mass was washed with 50ml of DI water followed by 10% w/w aqueous oxalic acid (40 ml). The organic layer was separated and distilled to afford oily to semisolid crude product. Then 20ml of acetone was added and stirred. Then reaction mass was cooled to 0-5°C followed by addition of 30ml of DI water. The reaction mass was stirred for 1 hour at 0-5°C and filtered. The wet cake was washed with DI water and dried under vacuum at 40-45°C to afford product as white to off-white solid.
Yield: 4.5 g (90% w/w); HPLC purity: 99.11%
Example 11: Preparation of compound of Formula-VI’
130 ml of Toluene was added to 10g of compound of Formula-VIII’’ and cooled to 0-5°C. 6.7g of CDI was added followed by addition of 5.3g of triethylamine. Raised reaction mass temperature to 40-45°C and stirred. The reaction mass was cooled to 0-5°C and 22.1g of methane sulfonic acid was added to it. Raised the reaction temperature to 25-35°C and stirred. 20 ml of 10% w/w aqueous potassium carbonate solution was added to the reaction mass and stirred for 30-60 minutes and layers were separated. The organic layer was washed with 10% aqueous oxalic acid solution followed by DI water. The organic layer was separated and distilled to afford crude product. Then 20ml of acetone was added to it at 25-30°C and stirred. Then reaction mass was cooled to 0-5°C followed by addition of 30ml of DI water. The reaction mass was stirred for 1 hour at 0-5°C and filtered. The wet cake was washed with 10 ml of DI water and dried under vacuum at 40-45°C to afford product as white to off-white solid.
Yield: 7.2g (90% w/w); HPLC purity: 99.58%
Example 12: Preparation of compound of Formula-V’
50ml of Isopropanol. 50ml of DI water, 1.1g of triethylamine, 7.6g of sulfur trioxide-trimethylamine complex and 10g of compound of Formula-VI’ was taken into hydrogenation reactor at 25-35°C. The reactor was flushed with nitrogen and 1.0 g of 10% w/w Pd/C was added to the reactor. The reactor was sealed and 1-2 Kg/cc hydrogen pressure was given. The reaction was stirred at 25-35°C. The reaction mass was filtered through a hyflo bed and washed with 20ml of DI water. The filtrate was washed with 50ml of ethyl acetate. The aqueous layer pH was adjusted to 6.5-7.5 and extracted with methylene dichloride. The organic layer was distilled to get crude product. Then 20ml of methyl isobutyl ketone was added to crude product and stirred. Cooled the reaction mass to 0-5°C and 80ml of methyl tert-butyl ether (MTBE) was added and stirred the reaction mass. Then solid was filtered and washed with 10ml of MTBE and dried under vacuum at 35-40°C to afford product as white to off-white solid.
Yield: 8.9g (92% w/w); HPLC purity: 99.20%
1H NMR (DMSO-d6, 400 MHz, dppm): 1.12-1.18 (t, 3H), 1.60-1.63 (m, 2H), 1.81-1.84 (m, 1H), 2.03-2.06 (m, 1H), 2.90-3.00 (m, 2H), 3.66-3.69 (d, 1H), 3.79 (broad, 1H), 4.23-4.27 (q, 2H), 8.6 (broad s, 1H);
13C NMR (DMSO-d6, 400 MHz, dppm): 13.40, 14.31, 18.05, 19.15, 20.51, 23.05, 46.89, 57.51, 59.55, 62.2, 165.96, 171.48; FTIR peaks (cm-1): 3442.9, 2986.4, 2910.2, 1726.1, 1695.3, 1475.1, 1274.0, 1222.2, 1142.2, 1043.5, 1021.1, 843.5, 713.5, 646.2, 610.6.;
m/z: 295.10 (M+H, free acid).
Example 13: Preparation of compound of Formula-IV’ (TBA salt)
30 ml of IPA was added to 10 g of compound of Formula-V’. Then Tetrabutyl ammonium acetate (15.3 g) was dissolved in 15 ml of water and added to the reaction mass then stirred for 2-3 hours. The reaction mass was diluted with water and extracted with DCM then washed with 5% brine. The organic layer was distilled to obtain crude product. Then crude product was taken along with 20ml of IPA and 60 ml of MTBE. Cooled the reaction mass to 0-5°C and stirred for 3-4 hours. Solid was filtered and wet material was dried under vacuum at 40-45° to afford product as white to off-white solid.
Yield: 17.2 g (92% w/w); HPLC Purity: 99.28%
1H NMR (DMSO-d6, 400 MHz, dppm): 0.89-0.92 (t, 12H), 1.10-1.15 (t, 3H), 1.20-1.31 (m, 8H), 1.50-1.65 (m, 10H), 1.80-1.84 (m, 1H), 2.01-2.05 (m, 1H), 2.92-3.03 (m, 2H), 3.18-3.23 (t,8H), 3.70-3.76 (d, 1H), 3.78 (broad, 1H), 4.23-4.28 (q, 2H);
13C NMR (DMSO-d6, 400 MHz, dppm): 13.40, 14.31, 18.05, 19.15, 20.51, 23.05, 46.89, 57.51, 59.55, 62.2, 165.96, 171.48;
FTIR (cm-1): 3442.9, 2948.6, 2923.6, 1730.7, 1698.4, 1475.0, 1276.3, 1259.2, 1240.5, 1169.6, 1063.5, 1022.6, 713.5,
m/z: 295.10 (M+H, free acid).
Example 14: Preparation of compound of Formula-III
50 ml of methanol was added to 10g of compound of Formula-V’ at RT. Then 30ml of 7M methanolic ammonia was added to it and stirred for 20-30 hours. Then reaction mass was diluted with 10ml of water and distilled under vacuum. The crude was dissolved in 80ml of DI water and washed with 60ml of n-butyl acetate. Aqueous layer pH was adjusted to 6.5-7.0pH with dilute acetic acid and extracted with methylene dichloride (2*50 ml). Methylene dichloride layer was concentrated to dryness to afford product as off-white solid to semisolid.
Yield: 8.6 g (90% w/w); HPLC Purity: 99.97%
Example 15: Preparation of compound of Formula-III
30 ml of methanol was added to 10g of compound of Formula-IV’ (TBA salt) at room temperature. Then 15ml of 7M methanolic ammonia was added to it and stirred for 20-30 hours. Then reaction mass was diluted with 10ml of water and distilled the methanol under vacuum. The crude was dissolved in 80ml of DI water and washed with 60ml of n-butyl acetate. Aqueous layer pH was adjusted to 6.5-7.0 pH with dilute acetic acid and extracted with methylene dichloride. Methylene dichloride layer was concentrated to dryness to afford product as off-white solid to semisolid.
Yield: 4.1 g (85% w/w); HPLC Purity: 99.98%
Example 16: Preparation of compound of Formula-II (TBA Salt)
Compound Formula-III (10g) prepared was dissolved in 100 ml of DI water and cooled to 0-5°C. 20ml of tetra butyl ammonium acetate solution (40% in water) was slowly added at 0-5°C and stirred for 2 hours. Then extracted with DCM and distilled to obtain crude product which was dissolved in 15ml of MIBK. Then 40ml of MTBE was added to it. The reaction mass was cooled to 0-5°C and stirred for 2-3 hours. Solid was filtered and washed with 15ml of MTBE. Wet product was taken with 20ml of Isopropanol and 55 ml of MTBE. Cooled the reaction mass to 20-30°C and stirred for 3-4 hours. Solid was filtered and washed with 20 ml of MTBE. Wet material was dried under vacuum at 40-45° to afford product as white to off-white solid.
Yield: 18.5 g (97% w/w); HPLC Purity: 99.85%
Example 17: Preparation of Avibactam Sodium
1000 ml of ethanol was added to 10g of compound of Formula-II (TBA salt) at 25-30°C and stirred the reaction mass and filtered through micron filters. Then 6.5g of sodium-2-ethyl hexanoate was dissolved in ethanol and filtered through micron filter. This solution was slowly added to the above reaction mass at 25-30°C and stirred for 60-90 min, filtered under nitrogen blanket and washed with chilled ethanol. Wet material was dried under vacuum at 40-45°C to afford Avibactam sodium as white to off-white solid.
Yield: 0.52g (92% w/w); HPLC purity: 99.96%

,CLAIMS:1. A process for the preparation of Avibactam of Formula III or Avibactam sodium of Formula I

comprising the steps of:
(i) converting compound of Formula VI to compound of Formula V;

wherein R1 is C1-C5 alkyl;
(ii) converting compound of Formula V to Avibactam of Formula III; and
(iii) optionally converting Avibactam of Formula III to Avibactam sodium of Formula I.

2. The process as claimed in claim 1, wherein step (i) comprises debenzylation and sulfonation.

3. The process as claimed in claim 1, wherein step (ii) comprises
(i) direct conversion; or
(ii) with or without isolation of salt of Formula IV.

wherein R1 is C1-C5 alkyl; and
Salt in Formula IV is selected from amine salts and metal salts selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt.

4. A compound of Formula V or its salt of Formula IV.

Wherein R1 is C1-C5 alkyl; and
Salt in Formula IV is selected from amine salts and metal salts selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt.

5. A process for the preparation of compound of Formula V or its salt of Formula IV

Wherein R1 is C1-C5 alkyl; and
Wherein Salt in Formula IV is selected from amine salts and metal salts selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt comprising the steps of:
(i) converting compound of Formula VI to compound of Formula V; and

(ii) optionally converting compound of Formula V to its salt of Formula IV.

6. The process as claimed in claim 5, wherein step (i) comprises debenzylation and sulfonation.

7. Use of compound of Formula V or its salt of Formula IV for the preparation of Avibactam of Formula III or Avibactam sodium of Formula I.


Wherein R1 is C1-C5 alkyl; and
Salt in Formula IV is selected from amine salts and metal salts selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt.

8. A process for the preparation of Avibactam of Formula III or Avibactam sodium of Formula I

comprising the steps of:
(i) converting compound of Formula X or its salt of Formula IX to compound of Formula VI;

wherein R1 is C1-C5 alkyl; and
salt in Formula IX is selected from the group comprising of oxalate, citrate, tartrate, acetate, sulfate, hydrochloride, p-toluene sulfonate;
(ii) converting compound of Formula VI to compound of Formula V;

(iii) optionally converting compound of Formula V to its salt of Formula IV;

Wherein Salt in Formula IV is selected from amine salts and metal salts selected from the group comprising of TBA (Tetrabutyl ammonium salt), Sodium salt, Triethylamine salt, Dicyclohexyl amine salt;
(iv) converting compound of Formula V or salt of Formula IV to Avibactam of Formula III; and
(v) optionally converting Avibactam of Formula III to Avibactam sodium of Formula I.

9. The process as claimed in claim 8, wherein step (i) comprises
(a) direct conversion; or
(b) with or without isolation of intermediate compound of Formulae VIII and VII

wherein HX in Formula VII is selected from the group comprising of HCl, H2SO4, H3PO4, HNO3 AcOH, p-Toluenesulfonic acid.