An improved process for the preparation of avibactam and intermediate thereof

Abstract

The present invention relates to an improved process for the preparation of Avibactam or a pharmaceutically acceptable salt thereof, particularly the present invention relates to process for the preparation of a bridged ester intermediate of Formula I, wherein R1 is a hydroxy protecting group which is a key intermediate for Avibactam or a pharmaceutically acceptable salt thereof. The present invention also relates to the crystalline form of intermediates used for the synthesis of Avibactam or a pharmaceutically acceptable salt thereof. The invention also provides improved processes for the preparation of Avibactam or a pharmaceutically acceptable salt, using the bridged ester compound of formula I prepared by the process of the present invention.

Description

[0001] AN IMPROVED PROCESS FOR THE PREPARATION OF AVIBACTAM AND INTERMEDIATE THEREOF

[0002] CROSS REFERENCE TO RELATED PATENT APPLICATION(S)

[0003] This patent application claims the benefit of Indian Patent Application No. IN202311051633, filed on 01 Aug. 2023, which is incorporated by reference herein in its entirety.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to an improved process for the preparation of Avibactam or a pharmaceutically acceptable salt thereof, particularly the present invention relates to a process for the preparation of a bridged ester intermediate of Formula I, wherein R1is a hydroxy protecting group which is a key intermediate in the synthesis of Avibactam or a pharmaceutically acceptable salt thereof.

[0006] The present invention also relates to a crystalline form of intermediates used for the synthesis of Avibactam or a pharmaceutically acceptable salt thereof. BACKGROUND OF THE INVENTION

[0007] Avibactam is a non-beta-lactamase inhibitor and is reported to have no antibacterial activity at clinically relevant doses. However, Avibactam protects beta-lactam antibiotics from degradation by beta lactamase enzymes and therefore maintains the antibacterial activity of beta-lactam antibiotics. It is therefore useful in conjunction with beta-lactam antibiotics for the treatment of bacterial infections.

[0008] The chemical name ofthe Avibactam sodium is (1R,2S,5R) -6-sulfonyloxy-7-oxo-l, 6-azabicyclo

[0009] [3.2.1] octane-2 -formamide monosodium salt, and the structure is shown in the formula. Avibactam sodium is marketed in a combination of the beta-lactamase inhibitor Avibactam sodium and a cephalosporin (ceftazidime) under the trade name AVY CAZ®, which is indicated for the treatment of patients of 18 years or older with the infections caused by designated susceptible microorganisms: complicated intra-abdominal infections (cIAI), used in combination with metronidazole and complicated urinary tract infections (cUTI), including Pyelonephritis.

[0010] Avibactam sodium is disclosed in W02002010172, which provides a process wherein a double- chiral piperidine derivative is used as starting material to prepare Avibactam via selective protection of free amine, inversion of configuration on chiral hydroxyl group, deprotection of protected amine, urea-cyclization using diphosgene, deprotection of allyl protecting group and simultaneous debenzylation followed by sulfation (of oxime) to give about 12% yield; which is then transformed to Avibactam sodium by employing DOWEX™ 50WX8 resin as a source of sodium in acetone-water mixture.

[0011] In the above processes, after the dinitrogen heterocyclic ring is constructed, the compound has an azabicyclo [3.2.1] structure, and carbonyl groups connected between two rings are subjected to larger torsion tension. Due to this, subsequent hydrolysis and condensation processes are easily attacked by nucleophilic reagents, and thereby causing ring opening decarbonylation as a side reaction, and the product needs to be purified by a column. Thus, the overall yield is further affected.

[0012] The process provided in WO2011042560 is similar to the process described in W02002010172 except it involves benzyl ester instead of allyl ester. There are several literature reports on the synthesis of Avibactam sodium, and two types of preparation routes are adopted according to a cyclization strategy: 1) first generation of carbamide ring and then amidation 2) first amidation and then generation of carbamide ring.

[0013] The bridge ring structure formed after cyclisation is unstable under acid and alkali conditions and may generate impurities with large polarity, which are difficult to purify. Specifically, by employing the second strategy (amidation first), there are high chances of formation of following impurity, which is difficult to remove from the desired product. Thus, the second strategy is not amenable from industrial point of view.

[0014] The bridged ester intermediate that is formed after generation of carbamide ring by employing the first strategy is an important intermediate for the synthesis of Avibactam or a pharmaceutically acceptable salt thereof. There are various methods reported for making the bridged ester intermediate, all of which suffer from one or more drawbacks, as described below.

[0015] CN106866668A discloses a process for making ethyl (2S,5R)-6-(benzyloxy)-7-oxo-l,6- diazabicyclo[3.2. l]octane-2 -carboxylate, wherein the reaction of (2S,5R)-ethyl-5- ((benzyloxy)amino)piperidine-2 -carboxylate oxalate with triphosgene in an organic solvent results in urea cyclisation to give bridged ester intermediate; followed by a conversion to Avibactam in one-pot-process. A large number of by-products are accumulated in the reaction due to one-pot- process which gives the desired product in low yield and poor quality.

[0016] There are many other references which describe the synthesis of the bridged ester intermediate using diphosgene or triphosgene for the urea cyclisation, which is a highly toxic reagent.

[0017] CN111777607A reports a preparation method of ethyl (2S,5R)-6-(benzyloxy)-7-oxo-l,6- diazabicyclo[3.2. l]octane-2 -carboxylate by first neutralisation of (2S,5R)-ethyl-5- ((benzyloxy)amino)piperidine-2-carboxylate oxalate, reaction of Fmoc-Cl followed by carbonylation and internal urea cyclization. The bridged ester intermediate prepared by this process has poor product purity and is achieved in low yield (65-70%). During the process, a costly protective agent Fmoc-Cl is used, which increases the production cost. From the forgoing, it is apparent that the reported methods for the preparation of the bridged ester intermediate involve toxic reagents like diphosgene or triphosgene, are less atom efficient and involve expensive protecting groups, such as Fmoc-Cl, and also require stringent operational conditions like ion exchange chromatography, which is not only tedious but also results in significant yield loss. The prior art processes also require non-environmentally friendly solvents, tedious work up procedures and purification steps.

[0018] Thus, there remains a need to provide an atom efficient and industrially viable synthetic process for the bridged ester intermediate, which can overcome the drawbacks of the prior art and thereby provide the desired product in high yield and high purity.

[0019] Along with the process, isolation of intermediates in crystalline form also plays an important role during synthesis of an active pharmaceutical ingredient, such as Avibactam or a pharmaceutically acceptable salt thereof. Polymorphic forms of an intermediate can prove beneficial for a drugdeveloper because their physicochemical properties, such as energy, melting point, density, stability and in particular solubility, may offer an improvement to the quality of the final active pharmaceutical ingredient. Crystalline polymorphs possess different physicochemical properties because of their different lattice structures and / or different molecular conformations.

[0020] In view of this, the present application also provides crystalline forms of intermediates, used during the process of making Avibactam or a pharmaceutically acceptable salt thereof, to make the process commercial amenable for the isolation and purification of intermediates.

[0021] OBJECT OF THE INVENTION

[0022] It is an object of the present invention to overcome the disadvantages of the known processes for synthesis of Avibactam or a pharmaceutically acceptable salt thereof, thereby providing an improved synthetic method, which is amenable for industrial synthesis.

[0023] In another objective, the present invention provides an improved and commercially viable process for the bridged ester intermediate of formula I, which avoids the use of toxic reagents.

[0024] This improved process for the synthesis of bridged ester intermediates of formula I is also atom efficient.

[0025] In yet another objective, the present invention provides crystalline forms of intermediates used during the making of Avibactam or a pharmaceutically acceptable salt thereof. SUMMARY OF THE INVENTION

[0026] The present invention provides an improved, commercially viable, atom efficient process for the preparation of Avibactam or a pharmaceutically acceptable salt thereof. The process of the present invention is straightforward and cost effective, when implemented on industrial scale. In a first aspect, the present invention relates to a process for the preparation of bridged ester intermediate of formula I, wherein R1is a hydroxy protecting group comprising: a) treating a compound of formula II or salts thereof wherein R1is a hydroxy protecting group with a tert-butoxycarbonylation reagent to form tert-butoxy compound of formula III or salts thereof; wherein R1is a hydroxy protecting group b) reacting the compound of formula III or salts thereof with N,N ’-carbonyldiimidazole followed by treatment with an acid; and c) reacting the product of step b) with a base to obtain the compound of Formula I In a second aspect, the present application provides a process for the preparation of bridged ester intermediate of formula la, comprising: a) treating a compound of formula Ila or salts thereof with a tert-butoxycarbonylation reagent to form tert-butoxy compound of formula Illa or salts b) reacting the compound of formula Illa or salts thereof with N,N ’-carbonyldiimidazole followed by treatment with an acid; and c) reacting the product of step b) with a base to obtain the compound of Formula la. In a third aspect, the present application provides a crystalline form of bridged ester intermediate of formula la.

[0027] In a fourth aspect, the present application provides a crystalline form of formula Illa.

[0028] In a fifth aspect, the present application provides a process for preparation of Avibactam or a pharmaceutically acceptable salt thereof, comprising converting a bridged ester intermediate of formula I to Avibactam or a pharmaceutically acceptable salt thereof.

[0029] In a sixth aspect, the present application provides a process for converting a bridged ester intermediate of formula I to Avibactam or a pharmaceutically acceptable salt thereof; comprising: a) hydrolysing the bridged ester intermediate of formula I, followed by amination to obtain a compound of formula IV; wherein R1is a hydroxy protecting group b) deprotecting the compound of formula IV followed by reaction with a sulfonating agent and tetrabutylammonium acetate to obtain a compound of formula V; and c) treating the compound of formula V with a sodium source to obtain Avibactam or a pharmaceutically acceptable salt thereof.

[0030] In a seventh aspect, the present application provides a crystalline form of compound of formula IVa.

[0031] In an eight aspect, the present application provides a crystalline form of compound of formula V.

[0032] In a ninth aspect, the present application provides Avibactam, or a pharmaceutically acceptable salt thereof prepared by the process of the present application.

[0033] In a tenth aspect, the present application provides Avibactam or a pharmaceutically acceptable salt thereof containing less than 100 ppm of isopropyl alcohol and / or less than 700 ppm of ethanol.

[0034] DEFINITIONS

[0035] The following definitions are used in connection with the present application unless the context indicates otherwise.

[0036] The term “tert-Butoxycarbonylation reagent” refers to a reagent which replaces the hydrogen atom of an amine group with a tert-butoxycarbonyl group. Examples of tert-Butoxycarbonylation reagents include Di-tert-butyl dicarbonate, N-(tert-Butoxycarbonyloxy)phthalimide, 2-(tert- Butoxycarbonyloxyimino)-2 -phenylacetonitrile, 2-(tert-Butoxycarbonylthio)-4,6- dimethylpyrimidine, N-tert-Butoxycarbonylimidazole, / / V- But l Phenyl Carbonate, 1-tert- Butoxycarbonyl-l,2,4-triazole, and tert-Butyl Carbazate.

[0037] The term “protecting group” refers to a temporarily attached group to decrease reactivity of a functional group so that the protected functional group does not react under synthetic conditions to which the molecule is subjected, in one or more subsequent steps. For the present invention, examples of the hydroxy protecting group include benzyl, allyl, and p-methoxy benzyl.

[0038] The term “ambient temperature” refers to a temperature ranging from 20 - 25 °C.

[0039] The term “atom efficient” or “atom economy” refers to the conversion efficiency of a chemical process in terms of all atoms involved and desired product produced. Good atom economy means most of the atoms of the reactants are incorporated in the desired products and only small amounts of unwanted by-products are formed, reducing the economic and environmental impact of waste disposal. All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise.

[0040] In general, polymorphism refers to the ability of a substance to exist as two or more crystalline forms that have different spatial arrangements and / or conformations of molecules in their crystal lattices. Thus, “polymorphs” refer to different crystalline forms of the same substance in which the molecules have different spatial arrangements of the molecules, atoms, and / or ions forming the crystal. Different polymorphs may have different physical properties such as melting points, solubilities, X-ray diffraction patterns, etc.

[0041] Polymorphism may also include solvation or hydration products (also known as pseudo polymorphs) and amorphous forms.

[0042] The term "substantially the same" with reference to analytical characterization such as X-ray powder diffraction (XRPD) peak positions or TGA thermogram endothermic / exothermic peak positions means that typical peak position and intensity variability are considered. For example, one skilled in the art will appreciate that the peak positions (2 theta) will show some inter-apparatus variability, typically as much as 0.2°. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art and should be taken as qualitative measure only.

[0043] ABBREVIATIONS

[0044] XRPD X-ray powder diffraction

[0045] TGA Thermal gravimetric analysis

[0046] DSC Differential Scanning Calorimetry

[0047] HPLC High Performance Liquid Chromatography

[0048] Fmoc Fluorenylmethyloxycarbonyl t-Boc tert-butoxycarbonyl

[0049] CDI N, N ’-Carbonyldiimidazole

[0050] BRIEF DESCIPTION OF DRAWINGS

[0051] FIG. 1; is an illustration of a XRPD pattern of a crystalline form of the bridged ester intermediate of formula la FIG. 2; represents a thermal gravimetric (TGA) analysis of a crystalline form of the bridged ester intermediate of formula la

[0052] FIG. 3; represents a differential scanning calorimetric (DSC) analysis of a crystalline form of the bridged ester intermediate of formula la

[0053] FIG. 4; is an illustration of a XRPD pattern of a crystalline form of the compound of formula Illa

[0054] FIG. 5; represents athermal gravimetric (TGA) analysis of a crystalline form of the compound of formula Illa

[0055] FIG. 6; represents a differential scanning calorimetric (DSC) analysis of a crystalline form of the compound of formula Illa

[0056] FIG. 7; is an illustration of a XRPD pattern of a crystalline form of the compound of formula IVa

[0057] FIG. 8; represents athermal gravimetric (TGA) analysis of a crystalline form of the compound of formula IVa

[0058] FIG. 9; represents a differential scanning calorimetric (DSC) analysis of a crystalline form of the compound of formula IVa

[0059] FIG. 10; is an illustration of a XRPD pattern of a crystalline form of the compound of formula V

[0060] FIG.11 ; represents a thermal gravimetric (TGA) analysis of a crystalline form of the compound of formula V

[0061] FIG. 12; represents a differential scanning calorimetric (DSC) analysis of a crystalline form of the compound of formula V

[0062] DETAILED DESCRIPTION OF THE INVENTION

[0063] The below description explains the invention in detail and the best mode in which it is to be performed. This process has several advantages such as avoidance of toxic reagents, high atom efficiency and commercial viability.

[0064] In a first aspect, the present invention relates to a process for the preparation of a bridged ester intermediate of Formula I. wherein R1is a hydroxy protecting group

[0065] The process for the preparation of bridged ester intermediate of formula I, comprises: a) treating a compound of formula II or salts thereof wherein R1is a hydroxy protecting group with a tert-butoxycarbonylation reagent to form tert-butoxy compound of formula III or salts thereof; wherein R1is a hydroxy protecting group b) reacting the compound of formula III or salts thereof with N,N ’-carbonyldiimidazole followed by treatment with an acid; and c) reacting the resulting mixture of step b) with a base to obtain the compound of Formula I

[0066] Preferably hydroxy protecting group include benzyl, allyl, and p-methoxy benzyl.

[0067] The salt of compound of formula II used in step a) may be organic acid salts, wherein organic acid is selected from the group consisting of oxalic acid, malic acid and benezene sulfonic acid. The tert-butoxycarbonylation reagent used in step a) may be selected from the Di-tert-butyl dicarbonate, N-(tert-Butoxycarbonyloxy)phthalimide, 2-(tert-Butoxycarbonyloxyimino)-2- phenylacetonitrile, 2-(tert-Butoxycarbonylthio)-4,6-dimethylpyrimidine, N-tert-

[0068] Butoxy carbonylimidazole, / ert- Butyl Phenyl Carbonate, l-tert-Butoxycarbonyl-l,2,4-triazole, and / ert- Butyl Carbazate. Preferably the tert-butoxy carbonylation reagent is Di-tert-butyl dicarbonate.

[0069] Step a) may be carried out in the presence of a base.

[0070] The base used in the reaction may be an organic base selected from the group consisting of triethylamine, di-isopropyl ethylamine, and 4-dimethylaminopyridine; or an inorganic base selected from the group consisting of sodium bicarbonate, potassium bicarboante and potassium carbonate; the preferred base used in the reaction is triethylamine.

[0071] Step a) is carried out at a temperature of 0°C to 30°C, preferably at 15°C - 30°C, or even more preferably at ambient temperature. The reaction time is not particularly limited, but is preferably in the range of 30 minutes to 10 hours, preferably in the range of 1 hour to 5 hours.

[0072] In a preferred embodiment, the compound of formula II or salts thereof is reacted with di -tert-butyl dicarbonate to obtain the compound of formula III or salts thereof.

[0073] The salt of compound of formula III includes but is not limited to salt with organic acid selected from the group consisting of oxalic acid, malic acid and benezene sulfonic acid.

[0074] In a more preferred embodiment, the oxalic acid salt of compound of formula II is reacted with di- tert-butyl dicarbonate to obtain the compound of formula III. Preferably, the oxalic acid salt of compound of formula II is reacted with di-tert-butyl dicarbonate in presence of triethylamine in dichloromethane to obtain the compound of formula III.

[0075] The compound of formula III or salts thereof prepared by the process according to an aspect of the present invention may be isolated using conventional methods and may optionally be purified.

[0076] In an embodiment, the compound of formula III is isolated.

[0077] In another embodiment, the compound of formula III is used in situ for further reaction.

[0078] In step b) the compound of formula III or salts thereof is reacted with N,N ’-carbonyldiimidazole followed by treatment with an acid at a temperature of 15-70°C, preferably at 30-45°C. The reaction time is not particularly limited but is preferably in a range of 1 hour to 25 hours, more preferably in a range of 3 hours to 15 hours. The acid used in step b) is organic acid selected from the group consisting of methanesulfonic acid and trifluoroacetic acid or an inorganic acid selected from the group consisting of hydrochloric acid, preferably acid is methanesulfonic acid.

[0079] Treatment with an acid is carried out at temperature of 10-40°C, preferably at ambient temperature. The reaction time is not particularly limited but is preferably in the range of 30 minutes to 10 hours, more preferably in the range of 1 hour to 5 hours.

[0080] The product of step b) is reacted with a base to obtain the bridged ester intermediate of formula I.

[0081] In step c), the base used in the reaction is an organic base selected from the group consisting of triethylamine, diisopropyl ethylamine, 4-dimethylaminopyridine and di-ethylamine; or an inorganic base selected from the group consisting of sodium bicarbonate, potassium bicarbonate and potassium carbonate, preferably the base is triethylamine.

[0082] Step a) and / or Step b) and / or Step c) may optionally be carried out in a solvent.

[0083] The solvent used in this reaction is not particularly limited as long as it is a solvent that does not participate in the reaction but is suitable for allowing the reaction to proceed efficiently and further facilitating the isolation of the target compound. Suitable solvents include ethers such as tetrahydrofuran; aromatic hydrocarbons such as toluene; halogenated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and chlorobenzene; and any mixture thereof. Preferably the solvent used in this reaction is dichloromethane.

[0084] In a more preferred embodiment, the compound of formula III or salts thereof is reacted with N,N’- carbonyldiimidazole followed by treatment with methanesulfonic acid and then with triethylamine to obtain the bridged ester intermediate of formula I.

[0085] The bridged ester intermediate of formula I, prepared by a process according to the first aspect of present invention may be isolated using conventional methods and may optionally be purified.

[0086] In a preferred aspect, the bridged ester intermediate of formula I is purified using solvents selected from alcohol such as ethanol, isopropanol; hydrocarbon solvents such as n-heptane or mixture thereof.

[0087] In a second aspect, the present application provides a process for the preparation of the bridged ester intermediate of formula la, comprising: a) treating a compound of formula Ila or salts thereof with a tert-butoxycarbonylation reagent to form tert-butoxy compound of formula Illa or salts thereof, b) reacting the compound of formula Illa or salts thereof with N,N ’-carbonyldiimidazole followed by treatment with an acid, and c) reacting the product of step b) with a base to obtain the compound of Formula la.

[0088] In a third aspect, the present application provides a crystalline form of the bridged ester compound of formula la. The crystalline form of the bridged ester compound of formula la is characterized by at least one of the following: a. an X-ray powder diffraction (XRPD) pattern comprising peaks at about 6.3, 18.6 and 24.9 ± 0.2 degrees two-theta; b. an X-ray powder diffraction (XRPD) pattern substantially the same as depicted in Fig. 1; c. by a weight loss of about less than 0.2 % as measured by thermal gravimetric analysis (TGA); d. athermal gravimetric thermogram substantially the same as depicted in Fig. 2. e. by a peak at about 58 °C by Differential scanning calorimetry (DSC); and f. a differential scanning calorimetric thermogram substantially the same as depicted in Fig. 3.

[0089] Further, the inventors have found that the crystalline form of bridged ester compound of formula la, is easily isolated and may readily be prepared on a commercial scale with high purity and high yield.

[0090] In a fourth aspect, the present application provides a crystalline form of formula Illa.

[0091] The crystalline form of formula Illa is characterized by at least one of the following: a. an X-ray powder diffraction (XRPD) pattern comprising peaks at about 8.4, 10.4, 19.7 and 21.0 ± 0.2 degrees two-theta; b. an X-ray powder diffraction (XRPD) pattern substantially the same as depicted in Fig. 4; c. by a weight loss of about less than 0.1 % as measured by thermal gravimetric analysis (TGA); d. a differential scanning calorimetric thermogram substantially the same as depicted in Fig. 5 e. by a peak at about 70 °C by Differential scanning calorimetry (DSC); and f. a differential scanning calorimetric thermogram substantially the same as depicted in Fig. 6

[0092] The crystalline compound of formula Illa may be further characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 12.7, 13.4, 17.3, 22.5 and 24.3 ± 0.2 degrees two-theta.

[0093] Inventors have found that a crystalline form of formula Illa is easily isolated and may readily be prepared on a commercial scale with high purity and high yield.

[0094] The inventive process for preparing the bridged ester intermediate of formula I is based on the surprising finding that the use of both, the tert-butoxy protecting group, as well as N,N’- carbonyldiimidazole as a reagent for the cyclisation, results in the bridged ester intermediate of formula I in high yield and high purity as compared to the prior art.

[0095] It was also observed that the use of toxic reagents such as phosgene for the cyclisation results in the bridged ester intermediate of formula I of poor-quality having purity of less than 60% by HPLC, thus requiring further purification using column chromatography, which thereby reduces the yield to 40-60%. Interestingly, when inventors of the process and compounds described above tried the cyclisation reaction of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylic acid (no protection at the piperidine nitrogen) using carbodiimide, the reaction does not reach completion even after heating the reaction mixture over prolonged time. A comparison with different possible processes known in the art concerning the synthesis of the bridged ester intermediate of formula I and the process of the present application is tabulated below:

[0096] * Resulting product contains major dibenzofulvene (DBF) as by-product, so it was not possible to readily calculate actual yield It is evident from the comparative data that both tert-butoxy protection as well as use of N,N’- carbonyldiimidazole as a reagent, are crucial to yield desired product in high yield and high purity. Even as compared to other protecting groups such as Fmoc, use of tert-butoxy group makes the process of the present application more industrial viable, due to one or more of the following reasons: - tert-butoxy group is a more atom efficient and more cost-effective protecting group as compared to Fmoc group - by-products formed by deprotection of tert-butoxy group, as per the present invention, are gaseous in nature, so easy to remove during the process. However, the dibenzofulvene (DBF) by-product, formed in case of using an Fmoc group as protecting group, is very difficult to remove due to non-polar nature of both bridged ester intermediate of formula I as well as of dibenzofulvene (DBF) high yield and high purity of desired product.

[0097] Moreover, the process of the present application avoids use of toxic reagents such as diphosgene or triphosgene and doesn’t require time consuming column chromatography for purification.

[0098] The resulting bridged ester intermediate of formula I can be achieved with a yield of more than 70%, preferably more than 75%, and purity more than 95% by HPLC, preferably more than 98% by HPLC, more preferably more than 99% by HPLC.

[0099] The bridged ester intermediate of formula I may be converted to Avibactam or a pharmaceutically acceptable salt thereof using methods known in the art e.g. using a process described in W02002010172 or specifically by the process provided in the present application.

[0100] In a fifth aspect, the present application provides a process for preparation of Avibactam or a pharmaceutically acceptable salt thereof, comprising converting the bridged ester intermediate of formula I to Avibactam or a pharmaceutically acceptable salt thereof.

[0101] Preferably, the process for converting the bridged ester intermediate of formula I to Avibactam or a pharmaceutically acceptable salt thereof; comprises the following steps a) hydrolysing the bridged ester intermediate of formula I, followed by amination to obtain a compound of formula IV; wherein Ri is a hydroxy protecting group. b) deprotecting the compound of formula IV followed by reaction with a sulfonating agent and tetrabutylammonium acetate to obtain a compound of formula V; and c) treating the compound of formula V with a sodium source to obtain Avibactam or a pharmaceutically acceptable salt thereof

[0102] Hydrolysis in Step a) may be carried out in the presence of a base.

[0103] The base used in the reaction is organic base selected from the group consisting of 4- Dimethylaminopyridine; or an inorganic base selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably the base is lithium hydroxide.

[0104] Hydrolysis in step a) may optionally be carried out in a solvent.

[0105] The solvent used in this reaction is not particularly limited as long as it is a solvent that does not participate in the reaction but is suitable for allowing the reaction to proceed efficiently and further facilitating the isolation of the target compound. Suitable solvents include ketones, such as acetone, but also water, tetrahydro furan, ethanol or methanol. The preferred solvent in this reaction is acetone.

[0106] Amination in step a) may be carried out using a suitable reagent, such as, e.g., aqueous ammonia. The compound of formula IV may be isolated using conventional methods and optionally purified. In an embodiment, the compound for formula IV is isolated as a crystalline compound.

[0107] In another embodiment, bridged ester compound of formula la undergoes hydrolysis followed by amination reaction to form the compound of formula IVa.

[0108] In a seventh aspect, the present application provides a crystalline form of compound of formula IVa,

[0109] The crystalline form of formula IVa is characterized by at least one of the following: a. an X-ray powder diffraction (XRPD) pattern comprising peaks at about 6.9, 13.7 and 20.6 ± 0.2 degrees two-theta; b. an X-ray powder diffraction (XRPD) pattern substantially the same as depicted in Fig. 7; c. by a weight loss of about less than 0.1 % as measured by thermal gravimetric analysis (TGA); d. a thermal gravimetric thermogram substantially the same as depicted in Fig. 8. e. by a peak at about 169 °C by Differential scanning calorimetry (DSC); and f. a differential scanning calorimetric thermogram substantially the same as depicted in Fig. 9.

[0110] The crystalline compound of formula IVa may be further characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 17.4, 18.9 and 23.2 ± 0.2° degrees two- theta.

[0111] The inventors have found that this crystalline form of formula IVa is easily isolated and may readily be prepared on a commercial scale with high purity and high yield.

[0112] The process described above may further involve deprotecting the compound of formula IV followed by reaction with a sulfonating agent and tetrabutylammonium acetate to obtain a compound of formula V.

[0113] A deprotection reaction is carried out using palladium on carbon in presence of sulfur-trixoide trimethylamine complex.

[0114] This deprotection may optionally be carried out in presence of organic base such as triethylamine.

[0115] The solvent used in this reaction is not particularly limited as long as it is a solvent that does not participate in the reaction but is suitable for allowing the reaction to proceed efficiently and further facilitating the isolation of the target compound. Suitable solvents include water, isopropanol, ethanol, methanol, tetrahydrofuran; it is preferred that the solvent in this reaction is a mixture of isopropanol and water.

[0116] The compound of formula V may be isolated using conventional methods and optionally purified.

[0117] In an embodiment, the compound for formula V is isolated as a crystalline compound.

[0118] In another embodiment, the compound of formula IVa undergoes a deprotection followed by reaction with sulfonating agent and tetrabutylammonium acetate to form the compound of formula V.

[0119] In an eight aspect, the present application provides a crystalline form of compound of formula V,

[0120] The crystalline form of formula V is characterized by at least one of the following: a. an X-ray powder diffraction (XRPD) pattern comprising peaks at about 5.6, 7.9, 11.2, 17.7, and 23.2 ± 0.2 degrees two-theta; b. an X-ray powder diffraction (XRPD) pattern substantially the same as depicted in Fig. 10; c. by a weight loss of about less than 0.1 % as measured by thermal gravimetric analysis (TGA); d. a differential scanning calorimetric thermogram substantially the same as depicted in Fig. 11 e. by a peak at about 149 °C by Differential scanning calorimetry (DSC); and f. a differential scanning calorimetric thermogram substantially the same as depicted in Fig. 12.

[0121] The crystalline compound of formula V may be further characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 12.5, 16.8, 20.2, and 23.9 ± 0.2° degrees two-theta.

[0122] The inventors have found that this crystalline form of formula V is easily isolated and may readily be prepared on a commercial scale with high purity and high yield.

[0123] The compound of formula V is then converted to Avibactam or a pharmaceutically acceptable salt thereof.

[0124] In a ninth aspect, the present application provides Avibactam or a pharmaceutically acceptable salt thereof obtained from performing the process as described above.

[0125] In a tenth aspect, the present application provides Avibactam or a pharmaceutically acceptable salt thereof, containing less than 100 ppm of isopropyl alcohol and / or less than 700 ppm of ethanol, preferably less than 50 ppm of isopropyl alcohol and / or less than 600 ppm of ethanol, more preferably less than or equal 34 ppm of isopropyl alcohol and / or less than or equal 594 ppm of ethanol.

[0126] The methods for preparing the bridged ester intermediate of formula I and further conversion to Avibactam or a pharmaceutically acceptable salt thereof may be illustrated by way of the following examples, which in no way should be construed as limiting the scope of the invention.

[0127] EXPERIMENTAL

[0128] Detailed experimental parameters according to the present invention are provided by the following examples, which are intended to be illustrative and not limiting of all possible embodiments of the invention.

[0129] Instruments

[0130] XRPD

[0131] X-ray diffraction data is obtained using PANalytical, Model: EMPYREAN, CuKa radiation, wavelength 1.54 A. In the XRPD pattern provided in the drawings, relative Intensity (in counts) is shown on the vertical axis (y axis) and the degrees (20) is shown on the horizontal axis (x-axis).

[0132] TGA TGA measurement is performed using a TA TGA 550, temperature range room temperature to 300°C and 10°C / min. In the TGA thermogram provided in the drawings, Weight (mg) is shown on vertical axis (y-axis) and temperature (°C) is shown on the horizontal axis (x-axis).

[0133] DSC

[0134] DSC is performed using TA DSC 2500, temperature range 25°C to 300°C and 10°C / min. In the DSC thermogram provided in the drawings, heat flow is shown on the vertical axis (y axis) and temperature (° C) is shown on the horizontal axis (x-axis).

[0135] Reference Example 1: Preparation of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6- diazabicyclo[3.2.1]octane-2-carboxylate (using triphosgene)

[0136] A solution of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2 -carboxylic acid (5g) in acetonitrile (50 ml) at 0-5°C is treated with triethylamine (4.7g) for 5 minutes. Triphosgene (3.2g) was added to reaction mixture in 15 minutes at 0-5°C and stirred for 10 minutes. 4-Dimethylaminopyridine (0.33g) was added and reaction mixture was heated 20-25°C followed by stirring for 3 hours at 20-25°C. Reaction mixture was diluted by water (50 ml) and extracted with ethylacetate (50ml). Organic layer was washed by 5% aqueous solution of citric acid (50ml), saturated solution of sodium bicarbonate (50 ml) followed by brine solution (50 ml). Organic layer was distilled under vacuum. Oily mass was stripped out with n-hexane (25ml) to give 5.5 g of (2S,5R)-ethyl 6- (benzyloxy)-7 -oxo- 1 ,6-diazabicyclo [3.2. 1 ]octane-2 -carboxylate as oily mass with purity of 58,0 % by HPLC and was purified by column chromatography.

[0137] Reference Example 2: Preparation of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6- diazabicyclo[3.2.1]octane-2-carboxylate (without protecting piperidine nitrogen) To a solution of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylic acid (5 g) in dichloromethane (50 ml), diisopropylethylamine (3.4 ml) was added at 20-25°C. Reaction mixture was cooled to 5-10 °C and is treated with N,N' -Carbonyldiimidazole (3.79 g). Reaction mixture was heated to 20-25 °C followed by stirring for 3 hours. Diisopropylethylamine (3.4 ml) was added to reaction mixture, heated to 38-40°C and stirred for 3 hours. Reaction monitoring was checked by TLC and further heated overnight. Reaction was not completed.

[0138] Reference Example 3: Preparation of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6- diazabicyclo[3.2.1]octane-2-carboxylate (using Fmoc Protecting Group)

[0139] To a solution of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylate oxalate (100g) in ethylacetate (1000ml), sodium bicarbonate solution (47g in 1200ml demineralised water) was added at 20-25 °C and stirred. Layer were separated and aqueous layer again re-extracted with ethylacetate (500ml). Combined organic layer was washed with brine solution (500ml) and concentrated under vacuum to get the viscous mass (73g) of (2S,5R)-ethyl 5- ((benzyloxy)amino)piperidine-2 -carboxylic acid.

[0140] To a solution of (2S,5R)-ethyl 5 -((benzyloxy)amino)piperidine-2 -carboxylic acid (72g) in dichloromethane (360ml) and diisopropylethylamine (36.8g), Fmoc-Cl solution(70.5g Fmoc-Cl in 360ml dichloromethane) was added at 20-30°C and stirred for 40 minutes. N,N'- Carbonyldiimidazole (80g) was added under stirring at 10-15°C and stirred the reaction mixture for 20 hours at 20-25°C. Diethylamine (47.5g) was added at 20-25°C and stirred for 8 hours at 30- 35°C. Hydrochloric acid solution (106 g cone. Hydrochloric acid in 340 ml demineralised water) was added at 20-25°C to the reaction mixture. Settled the mass and organic layer was collected. Organic layer was washed with demineralised water (360ml) and brine solution (360ml). Organic layer was distilled and degassed at 40 °C under vacuum to get oily mass (165g). Diisopropylethylamine (360ml) was added to the oily mass and stirred for 15 minutes to crystalize the solid compound. The reaction mass was fdtered and filtrate was distilled under vacuum at 45 °C to get the 150 g of 2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2- carboxylate as oily mass with purity of 43.81% by HPLC.

[0141] Obtained product contains major dibenzofulvene (DBF) as by-product hence the actual yield can’t be readily [?] calculated.

[0142] Example 1: Preparation of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane- 2-carboxylate

[0143] Step I: Preparation of 1 -(tert-butyl) 2-ethyl (2.S'.5 / ?)-5-((bcnzyloxy) amino) piperidine- 1,2- dicarboxylate

[0144] Method A:

[0145] To a solution of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylate oxalate (600g) in dichloromethane (5400 ml), triethylamine (494.45 g) and di-tert-butyl dicarbonate (462.11 g) was added at 0-10°C and reaction mixture was stirred at 20-25 °C for 3-4 hours. Reaction mixture was diluted by water (3000ml) and organic layer was collected. The organic layer was washed with saturated solution of sodium bicarbonate (3000 ml). Resulting organic layer was distilled out at 30-35°C. Dichloromethane (750ml) and n-heptane (2250ml) was added to resulting product and stirred at 20 to 25°C for 10 to 15 minutes. Solid was filtered, washed with n-Heptane (750ml) and dried u / v at 35 to 40°C to give 1 -(tert-butyl) 2-ethyl (2.S'.5 / ?)-5-((bcnzyloxy) amino) piperidine- 1,2-dicarboxylate

[0146] Method B:

[0147] To a solution of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylate oxalate (600g) in dichloromethane (5400 ml), triethylamine (494.45 g) and di-tert-butyl dicarbonate (462.11 g) was added at 0-10°C and reaction mixture was stirred at 20-25 °C for 3-4 hours. Reaction mixture was diluted by water (3000ml) and organic layer was collected. The organic layer was washed with saturated solution of sodium bicarbonate (3000 ml). Resulting organic layer was distilled out up to ~200ml at 40-45 °C and at atmospheric pressure.

[0148] Step 2: (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylate ' '-carbonyldiimidazolc (528.0 g) was added to the solution of (2S,5R)-ethyl 5-((benzyloxy)tert- butyloxyamino)piperidine-2 -carboxylate in DCM obtained by step 1, method B and mixture was heated at 40-45°C for 15 hours. Mixture was cooled at 0-5°C, methanesulfonic acid (1408.7 g) was added into the reaction mixture and stirred at 20-25 °C for 4 hours. Reaction mixture was again cooled to 0-5°C, treated with triethylamine (1318.5g) and stirred for 4 hours at 30-35°C. Mixture was cooled to - 10 to -5°C and treated with aqueous hydrochloric acid (-35%, 690g of hydrochloric acid in 2400ml of demineralised water). Layer were separated and organic layer was washed with water (1200 ml). Resulting organic layer was distilled to give crude compound. Isopropanol (900ml) was added to crude compound at 35-40°C and distilled out the 300ml Isopropanol at 45- 50°C under vacuum. n-Heptane (600ml) was added to resulting mixture and cooled to the 0-5 °C. Mixture was stirred for 2 hours at 0-5°C and filtered. Resulting product was washed with precooled Isopropanol (150 ml), n-Heptane (150ml) and dried under vacuum to give 444g (89%) of (2S,5R)- ethyl 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2. l]octane-2 -carboxylate as solid having 99.93% purity by HPLC.

[0149] Example !: Preparation of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane- 2-carboxylate

[0150] To a solution of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylate oxalate (100g) in dichloromethane (900 ml), triethylamine (82.42 g) and di-tert-butyl dicarbonate (77 g) was added at 0-10°C and reaction mixture was stirred at 20-25 °C for 3-4 hours. Reaction mixture was cooled to 10-15°C, diluted by water (500ml) and organic layer was collected. The organic layer was washed with saturated solution of sodium bicarbonate (500 ml). Resulting organic layer was distilled out at 40-45°C at atmospheric pressure. Reaction mass was cooled at 5-10 °C and N,N'- carbonyldiimidazole (528.0 g) was added to it. Reaction mixture was heated at 40-45 °C for 15 - 17 hours. Mixture was cooled at 0-5 °C, methanesulfonic acid (1408.7 g) was added into the reaction mixture and stirred at 20-25 °C for 4 -5 hours. Reaction mixture was again cooled to 0- 5°C, treated with triethylamine (219.8g) and stirred for 4 -5 hours at 30-35°C. Mixture was cooled to -10 to -5 °C and treated with aqueous hydrochloric acid (-35%, 115g of hydrochloric acid in 400ml of demineralised water). Layer were separated and organic layer was washed with water (200 ml). Resulting organic layer was distilled to give crude compound. Isopropanol (150ml) was added to crude compound at 35-40°C and distilled out the 45ml - 50 ml Isopropanol at 45-50°C under vacuum. n-Heptane (100ml) was added to resulting mixture and cooled to the 0-5 °C. Mixture was stirred for 2 - 3 hours at 0-5°C and filtered. Resulting product was washed with precooled Isopropanol (25 ml), n-Heptane (25 ml) and dried under vacuum to give 63g (76%) of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2 -carboxylate as solid having >98% purity by HPLC.

[0151] Example 3: Preparation of (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2- carboxamide

[0152] A solution of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylate (350g) in Acetone (1750 mL) was cooled to -12 to -8°C. Precooled aq. Lithium hydroxide solution (52.9g in 875ml water) was added to the reaction mixture and stirred the reaction mixture at -12 to -5°C for 1 hour. The resulting mixture was stirred with pre-cooled aq. HC1 solution (prepared by dissolving 165 mL of cone. HC1 in 700 mL of DM water) at -12 to 0°C followed by addition of dichloromethane (1750ml) into the mixture. Layer were separated. Compound re-extracted using dichloromethane (1050ml). Combined organic layer was cooled to 0-5°C and treated with N-hydroxy succinimide (178.0 g) and l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide.hydrochloride (297.5 g) at 0-5°C. Reaction mixture was stirred for 3 hours and treated with 25% aq. ammonia solution (717g) at 0-10°C followed by sat. solution of sodium bicarbonate solution (prepared by dissolving 87.5g of sodium bicarbonate in 1050 ml of DM water) and organic layer collected. Again, organic layer was treated with the aq. HC1 solution and stirred the mixture for 5-10min and washed the organic layer with brine solution (1050ml). Organic layer was distilled the organic layer u / v below 35 °C till residual remaining volume was ~ 2100ml. Isopropanol (1750ml was added and distilled at 45°C till residual volume was 1050ml. Slurry was fdtered and washed with isopropanol (175ml) and dried u / v at 40-45°C to give 200g (63.5%) of (2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2- carboxamide with purity 99.7% by HPLC.

[0153] Example 4: Preparation of tetrabutylammonium (2S,5R)-2-carbamoyl-6-(benzyloxy)-7-oxo- 1 ,6-diazabicyclo [3.2.1] octane-6-yl sulf ate

[0154] To a suspension of (2S, 5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2. l]octane-2 -carboxamide (150g) in isopropanol (750 ml) and water (750 ml), sulphur trioxide-trimethylamine complex (91.02 g), triethylamine (91.02 g) and 10% Pd / C (Type-487) (3.75g) was added. Flushed the hydrogenator with nitrogen gas (~1.5-2.0 kg / cm2) for three times and flushed the hydrogenator with hydrogen gas (-1.0-1.5 kg / cm2) for three times. Filled the hydrogenator with hydrogen gas (-1.5-2.0 kg / cm2) and heated the mass at 30-37°C for 2 hours. Reaction mixture was cooled to 20-25 °C and released the hydrogen gas and flushed with the nitrogen gas. Acetic acid (8.18g) was added in the reaction mixture and fdtered through the celite and washed with water (300ml). n- Butylacetate ( 900ml) was added to the mixture and stirred for 10-20 min. Tetrabutylammonium acetate solution (-325 mL, dissolved Tetrabutylammonium acetate (213.63g) in DM water (225 mL) and Acetic acid (3.27g)) was added to aqueous layer followed by addition of dichloromethane (900ml). Resulting mixture was stirred for 10-15 minutes and layer were separated. Remaining Tetrabutylammonium acetate solution (125ml) was added into the aq. layer and stirred for 20-25 minutes and extracted with dichloromethane (450ml). Combined organic layer distilled till residual volume -600-630 mL and methylisobutylketone (1800ml) was added followed by distillation at 35°C till volume remains -1500-1530 ml. The resulting mixture was cooled, stirred for 1 hour at 0-5 °C, filtered and washed with methylisobutylketone (300ml). Resulting product was dried u / v at 35-40°C to give 232g (84%) of tetrabutylammonium (2S,5R)-2-carbamoyl-6-(benzyloxy)-7- oxo-1, 6-diazabicyclo[3.2.1]octane-6-yl sulfate with purity 99.99% by HPLC.

Claims

CLAIMS:

1. A process for the preparation of a bridged ester intermediate of formula I,wherein R1is a hydroxy protecting group comprising: a) treating a compound of formula II or salts thereofwherein R1is a hydroxy protecting group with a tert-butoxycarbonylation reagent to form a tert-butoxy compound of formula III or salts thereof;wherein R1is a hydroxy protecting group. b) reacting the compound of formula III or salts thereof with N, N ’-carbonyldiimidazole followed by treatment with an acid; and c) reacting the product of step b) with a base to obtain the compound of Formula I2. The process according to claim 1, wherein the hydroxy protecting group (R1) is selected from the group consisting of benzyl, allyl, and p-methoxy benzyl.

3. The process according to claim 1, wherein the hydroxy protecting group (R1) is benzyl.

4. The process according to claim 3, wherein the process for the preparation of a bridged ester intermediate of formula la,comprising: a) treating a compound of formula Ila or salts thereofwith a tert-butoxycarbonylation reagent to form tert-butoxy compound of formula Illa or salts thereof,b) reacting the compound of formula Illa or salts thereof with N,N ’-carbonyldiimidazole followed by treatment with an acid; and c) reacting the product of step b) with a base to obtain the compound of Formula la.

5. The process according to claim 1 or 4, wherein the salt of the compound of formula II, Ila or III is selected from the group consisting of oxalate, malate and benezene sulfonate.

6. The process according to claim 1 or 4, wherein the tert-Butoxycarbonylation reagent is selected from Di-tert-butyl dicarbonate, N-(tert-Butoxycarbonyloxy)phthalimide, 2-(tert- Butoxycarbonyloxyimino)-2-phenylacetonitrile, 2-(tert-Butoxycarbonylthio)-4,6- dimethylpyrimidine, N-tert-Butoxy carbonylimidazole, tert-Bv yl Phenyl Carbonate, 1-tert- Butoxy carbonyl- 1, 2, 4-triazole, and tert- Butyl Carbazate.

7. The process according to claim 1 or 4, wherein step a) is carried out in presence of a base.

8. The process according to claim 7, wherein the base is an organic base selected from the group consisting of triethylamine, di-isopropyl ethylamine, and 4-dimethylaminopyridine, or an inorganic base selected from the group consisting of sodium bicarbonate, potassium bicarbonate and potassium carbonate.

9. The process according to claim 1 or 4, wherein step a) is carried out at a temperature of 0-30°C for 30 minutes to 10 hours.

10. The process according to claim 1 or 4, wherein step a) is carried out at ambient temperature for 1 to 5 hours.

11. The process according to claim 1 or 4, wherein the compound of formula III is reacted with N,N ’-carbonyldiimidazole at a temperature of 15-70°C for 1 to 25 hours.

12. The process according to claim 1 or 4, wherein the compound of formula III is reacted with N,N ’-carbonyldiimidazole at a temperature of 30-45°C for 3 to 15 hours.

13. The process according to claim 1 or 4, wherein the acid in step b) is methanesulfonic acid trifluoroacetic acid, or hydrochloric acid.

14. The process according to claim 1 or 4, wherein the treatment with an acid is carried out at temperature of 10-40°C for 30 minutes to 10 hours.

15. The process according to claim 1 or 4, wherein the treatment with acid is carried out at ambient temperature for 1 to 5 hours.

16. The process according to claim 1 or 4, wherein the base in step c) is an organic base selected from the group consisting of triethylamine, diisopropyl ethylamine, 4-dimethylaminopyridine and di-ethylamine or an inorganic base selected from the group consisting of sodium bicarbonate, potassium bicarbonate and potassium carbonate.

17. The process according to claim 1 or 4, wherein step a) and / or step b) and / or step c) is carried out in presence of a solvent.

18. The process according to claim 17, wherein the solvent is selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, chlorobenzene and any mixture thereof.

19. A process for the preparation of Avibactam or a pharmaceutically acceptable salt thereof comprising converting the compound of formula I obtained by a process according to any of the preceding claims to Avibactam or a pharmaceutically acceptable salt thereof.

20. Avibactam or a pharmaceutically acceptable salt thereof prepared by the process according to claim 19.

21. Avibactam or a pharmaceutically acceptable salt thereof according to claim 20 containing less than 100 ppm of isopropyl alcohol and / or less than 700 ppm of ethanol.

22. A crystalline form of compound of formula la,characterized by at least one of the following: a. an X-ray powder diffraction (XRPD) pattern comprising peaks at about 6.3, 18.6 and 24.9 ± 0.2 degrees two-theta; b. an X-ray powder diffraction (XRPD) pattern substantially the same as depicted in Fig. 1; c. by a weight loss of about less than 0.2 % as measured by thermal gravimetric analysis (TGA); d. a thermal gravimetric thermogram substantially the same as depicted in Fig.

2. e. by a peak at about 58 °C by Differential scanning calorimetry (DSC); andf. a differential scanning calorimetric thermogram substantially the same as depicted in Fig.3.

23. A crystalline form of compound of formula Illa,characterized by at least one of the following: a. an X-ray powder diffraction (XRPD) pattern comprising peaks at about 8.4, 10.4, 19.7 and 21.0 ± 0.2 degrees two-theta; b. an X-ray powder diffraction (XRPD) pattern substantially the same as depicted in Fig. 4; c. by a weight loss of about less than 0.1 % as measured by thermal gravimetric analysis (TGA); d. a differential scanning calorimetric thermogram substantially the same as depicted in Fig.5 e. by a peak at about 70 °C by Differential scanning calorimetry (DSC); and f. a differential scanning calorimetric thermogram substantially the same as depicted in Fig.

624. The crystalline form of the compound of formula Illa according to claim 23, characterized by an X-ray powder diffraction (XRPD) pattern further comprising peaks at about 12.7, 13.4, 17.3, 22.5 and 24.3 ± 0.2 degrees two-theta.

25. The process according to claim 19, wherein the process for converting the bridged ester intermediate of formula I to Avibactam or a pharmaceutically acceptable salt thereof, comprises: a) hydrolysing the bridged ester intermediate of formula I followed by amination to obtain a compound of formula IV;wherein R1is a hydroxy protecting group b) deprotecting the compound of formula IV followed by reaction with a sulfonating agent and tetrabutylammonium acetate to obtain a compound of formula V; andc) treating the compound of formula V with a sodium source to obtain Avibactam or a pharmaceutically acceptable salt thereof.

26. A crystalline form of compound of formula IVa,characterized by at least one of the following: a. an X-ray powder diffraction (XRPD) pattern comprising peaks at about 6.9, 13.7 and 20.6 ± 0.2 degrees two-theta; b. an X-ray powder diffraction (XRPD) pattern substantially the same as depicted in Fig. 7; c. by a weight loss of about less than 0.1 % as measured by thermal gravimetric analysis (TGA);d. a thermal gravimetric thermogram substantially the same as depicted in Fig.

8. e. by a peak at about 169 °C by Differential scanning calorimetry (DSC); and f. a differential scanning calorimetric thermogram substantially the same as depicted in Fig.9.

27. The crystalline form of the compound of formula IVa according to claim 26, wherein Formula IVa is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 6.9, 13.7 and 20.6 ± 0.2 degrees two-theta and further comprising peaks at about 17.4, 18.9 and 23.2 ± 0.2° degrees two-theta.

28. A crystalline form of compound of formula V,characterized by at least one of the following: a. an X-ray powder diffraction (XRPD) pattern comprising peaks at about 5.6, 7.9, 11.2, 17.7, and 23.2 ± 0.2 degrees two-theta; b. an X-ray powder diffraction (XRPD) pattern substantially the same as depicted in Fig. 10; c. by a weight loss of about less than 0.1 % as measured by thermal gravimetric analysis (TGA); d. a differential scanning calorimetric thermogram substantially the same as depicted in Fig. 11; e. by a peak at about 149 °C by Differential scanning calorimetry (DSC); and f. a differential scanning calorimetric thermogram substantially the same as depicted in Fig.12.

29. The crystalline form of the compound of formula V according to claim 28, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 5.6, 7.9, 11.2, 17.7, and 23.2 ± 0.2 degrees two-theta and further comprising peaks at about 12.5, 16.8, 20.2, and 23.9 ± 0.2° degrees two-theta.

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