Process to prepare avibactam tomilopil

Abstract

The present invention is directed to improved processes for making the avibactam prodrug known as avibactam tomilopil or ethyl 3-[((1R,2S,5R)-2-carbamoyl-7-oxo-1,6- diazabicyclo[32.1]oct-6-yl)oxysulfonyloxy]-2,2-dimethylpropanoate of formula (I) and the spherical agglomerate particles resulting from said processes that are useful in large scale manufacturing.

Description

[0001] PC073163A

[0002] PROCESS TO PREPARE AVIBACTAM TOMILOPIL

[0003] Background of the Invention

[0004] The present invention is directed to efficient processes for preparing avibactam tomilopil and novel spherical agglomerate particles of avibactam tomilopil produced from said processes. Avibactam tomilopil is an orally bioavailable prodrug of avibactam, which is a potent beta lactamase inhibitor that is one of the active ingredients in the product Zavicefta®. Avibactam tomilopil is currently in development in combination with ceftibuten as an oral antibiotic to treat certain bacterial infections. Avibactam tomilopil and processes for its preparation have been described in WO 2018 / 208557 and E.M. Gordon, M.A.J. Duncton, and M.A. Gallop, J. Med Chem. 2018, 61 , 10340-10344.

[0005] Avibactam tomilopil (hereafter “AVP”) is also known as ethyl 3-[((1 R,2S,5R)-2- carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1 ]oct-6-yl)oxysulfonyloxy]-2,2- dimethylpropanoate which is of formula:

[0006] It is known to have unusual inherent physical properties because it exits as a crystalline mesophase, an ordered phase with long range 2-dimensional order [Cui, Y. A material science perspective of pharmaceutical solids. International Journal of Pharmaceutics 2007, 339 (1 ), 3-18; Chakravarty, P.; Bates, S.; Thomas, L. Identification of a Potential Conformationally Disordered Mesophase in a Small Molecule: Experimental and Computational Approaches. Molecular Pharmaceutics 2013, 10 (8), 2809-2822], Additionally, avibactam tomilopil and key avibactam tomilopil intermediates have a low thermal onset and highly energetic thermal composition with strong pressure increase (i.e. , self-reactive). The known process to make avibactam tomilopil calls for isolation of key certain high-energy intermediates which presents safety concerns that are not practical or feasible for commercial scale manufacturing. Moreover, the high therapeutic dose anticipated for avibactam tomilopil, based on ICH guidelines, requires low impurity limits which are not achievable with the known process as described in Gordon et al. Accordingly, there remains a need for a scalable, efficient, safe, and robust process to make avibactam tomilopil in a high degree of purity. The present invention addresses these technical challenges with novel processes having increased robustness and yields and which produce novel spherical agglomerates of avibactam tomilopil that are useful in processing and isolation at commercial scale. Spherical agglomeration is a particle engineering technique where crystallization and agglomeration occur simultaneously yielding agglomerated crystals in a compacted, spherical form (Powder Technology 2018, 326, 327-343).

[0007] The processes of the present invention are distinguished over the known process to make avibactam tomilopil in that the two key reactions, hydrogenation and coupling reactions, are telescoped so as not to isolate high-energy, unstable, intermediates between those reactions.

[0008] Summary of the Invention

[0009] The present invention provides, in part, processes for manufacturing avibactam tomilopil and the spherical agglomerate particles produced from said processes. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description.

[0010] Specifically, the present invention provides two synthetic processes for preparing avibactam tomilopil each of which contains several process modifications compared to the previously disclosed processes in the literature and involves two route options - “Batch” and “Flow”.

[0011] This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.

[0012] According to an embodiment of the invention, there is provided a process for preparing avibactam tomilopil comprising debenzylating AVI-BU of formula: AVI-BU though a hydrogenation reaction in the presence of a palladium catalyst, a hydrogen donor, and a solvent to obtain the compound of formula III: followed by coupling the compound of formula III with the compound of formula IVb: in the presence of a base and a halide scavenger; wherein the compound of formula III is never isolated.

[0013] Described below are embodiments of the invention.

[0014] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0015] Brief Description of Drawings

[0016] FIG. 1 and FIG. 2 show SEM electron microscope images at three different magnifications of the spherical agglomerates produced in Example 2.

[0017] FIG. 3 shows SEM electron microscope images at two different magnifications of the specifical agglomerates produced in Example 1 .

[0018] FIG. 4 shows a polarized light microscope (PLM) image of the spherical agglomerates produced in Example 4.

[0019] FIG. 5 shows scanning electron microscope (SEM) images at two different magnifications of the spherical agglomerates produced in Example 4.

[0020] FIG. 6, FIG. 7 and FIG. 8 compares scanning electron microscope (SEM) images of avibactam tomilopil. The two images of FIG. 6 were produced using typical antisolvent crystallization methods similar to the method described in Gordon et al. (i.e. , the method where the unstable intermediate of formula III was isolated) followed by high shear wet milling, and which does not produce spherical agglomerates. The four images of FIG. 7 and FIG. 8 are the spherical agglomerates produced in Example 4. The two images of FIG. 8 show a cross section of a spherical agglomerate that show the void from the pathway of crystallization it takes: formation of oil droplet of AVP that crystallizes into flakes that come together in the agglomerate around the now empty space left by the droplet.

[0021] Detailed Description of the Invention

[0022] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. The following embodiments, E1 to E28 are representative embodiments of the present invention which should be construed in a non-limiting manner.

[0023] E1 is a process for preparing avibactam tomilopil comprising debenzylating AVI- BU of formula: AVI-BU though a transfer hydrogenation reaction in the presence of a palladium catalyst, a hydrogen donor, and a solvent to obtain the compound of formula III: followed by coupling of the compound of formula III with the compound of formula IVb: IVb in the presence of a base and a halide scavenger; wherein the compound of formula III is never isolated.

[0024] E2 is the process of embodiment E1 wherein the hydrogen donor is selected from the group consisting of formic acid, potassium formate, ammonium formate, amine formate, and triethylsilane; wherein the solvent is acetone, methyl ethyl ketone, isopropanol, or mixtures thereof; and wherein the palladium catalyst is on a solid support of alumina or carbon; or the palladium catalyst is selected from Pd(OAc)2, PdCl2, and Pd(dba)3.

[0025] E3 is the process of embodiment E1 or E2 wherein the base is selected from 1 ,4 diazabicyclo[2.2.2.]octane (DABCO), quinuclidine and tetramethylethylenediamine (TMEDA); and wherein the solvent is selected from acetone and methyl ethyl ketone.

[0026] E4 is the process of embodiment E1 or E2 wherein the base is selected from 1 ,1 ,3,3-tetramethylguanidine (TMG), 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), and 7- methyl-1 ,5,7, triazabicyclo(4.4.0)dec-5-ene (MTBD); and wherein the solvent is isopropanol.

[0027] E5 is the process of any one of the embodiments E1 to E4 wherein the halide scavenger is selected from the group consisting of potassium triflate (K-OTf), sodium triflate (Na-OTf), potassium hexafluorophosphate (K-PFe), sodium hexafluorophosphate (Na-PFe), and sodium tetrafluoroborate (NaBF4).

[0028] E6 is the process of embodiment E1 wherein the palladium catalyst is on a solid support of alumina, the hydrogen donor is formic acid, the base is 1 ,4 diazabicyclo[2.2.2.]octane, the solvent is methyl ethyl ketone, and wherein the halide scavenger is sodium triflate (Na-OTf).

[0029] E7 is a process for preparing avibactam tomilopil comprising debenzylating the compound of formula AVI-BU through a hydrogenation reaction in a packed bed gasliquid flow reactor packed in the presence of a heterogeneous catalyst, a hydrogen source, and a solvent to obtain the compound of formula III, followed by coupling of the compound of formula III with a compound of formula IVb in a plug flow reactor in the presence of a base; wherein the compound of formula IVb is introduced into the reactor as a stream that is neat or synthesized continuously; and wherein the compound of formula III is never isolated. E8 is the process of embodiment E7 wherein the solvent is a mixture of acetonitrile and isopropanol or a mixture of dimethylformamide and isopropanol; wherein the catalyst is palladium supported on carbon or alumina solid supports; wherein the hydrogen source is hydrogen gas or triethylsilane, and wherein the base is 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1 ,1 , 3, 3- tetramethylguanidine (TMG), 7-methyl-1 ,5,7, triazabicyclo(4.4.0)dec-5-ene (MTBD), or triazabicyclodecene (TBD).

[0030] E9 is the process of embodiment E8, wherein the solvent is a mixture of acetonitrile and isopropanol, the catalyst is palladium supported on carbon, the hydrogen source is hydrogen gas, and the base is 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

[0031] E10 is a process for preparing avibactam tomilopil comprising the steps (a)-(c):

[0032] (a) debenzylating the compound of formula AVI-BU by reacting it with hydrogen gas in the presence of a palladium on carbon heterogeneous catalyst to obtain the compound of formula III;

[0033] (b) isolating the compound of formula III as a monohydrate with water, methyl tert-butyl ether (MTBE), and n-heptane; and

[0034] (c) coupling the monohydrate compound of formula III obtained in step (b) with the compound of formula IVb in the presence of 1 ,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) in isopropanol and water.

[0035] E11 is the process of any one of the embodiments E1 to E10, wherein the compound of formula AVI-BU is recrystallized with hot filtration prior to debenzylating.

[0036] E12 is the process of embodiment E11 , wherein hot filtration occurs in a solvent comprising tetrahydrofuran (THF) and water at a temperature of at least about 50°C.

[0037] E13 is the process of embodiment E12 wherein the hot filtration solvent has a ratio of tetrahydrofuran (THF) and water that is of about 1 to 1 by volume; and wherein the compound of formula AVI-BU is then isolated in tetrahydrofuran (THF) and water with a ratio of about 1 to 4 by volume. E 14 is the process of any one of the embodiments E1 to E13 wherein the compound of formula IVb is prepared from a synthesis that is run neat.

[0038] E15 is the process of any one of the embodiments E1 to E13 wherein the compound of formula IVb is prepared from a synthesis that is run as a continuous process with a base and a solvent.

[0039] E16 is the process of any one of the embodiments E1 to E15 wherein avibactam tomilopil is subsequently crystallized by dissolving avibactam tomilopil in isopropyl acetate or 2-methyl tetrahydrofuran; optionally performing an aqueous work up followed by distilling off residual water; and isolating avibactam tomilopil with heptane.

[0040] E17 is the process of embodiment E16 wherein avibactam tomilopil is further recrystallized by dissolving avibactam tomilopil in 2-methyl tetrahydrofuran, methyl tertbutyl ether (MTBE), and water; performing an aqueous work up; distilling methyl tertbutyl ether (MTBE) and water off such that water is at a level of less than about 0.3% w / w water; and isolating avibactam tomilopil with heptane.

[0041] E18 is a process to recrystallize avibactam tomilopil comprising the steps of dissolving avibactam tomilopil in 2-methyl tetrahydrofuran, methyl tert-butyl ether (MTBE), and water; performing an aqueous work up; distilling methyl tert-butyl ether (MTBE) and water off such that water is at a level of less than about 0.3% w / w water; and isolating avibactam tomilopil with heptane.

[0042] E19 is avibactam tomilopil spherical agglomerates obtainable by the process according to any one of the embodiments E1 to E17.

[0043] E20 is avibactam tomilopil in the form of spherical agglomerates.

[0044] E21 is the spherical agglomerates of embodiment E19 or E20, wherein the spherical agglomerates are characterized by an opaque circular shape as observed in the polarized light microscopy image of FIG. 4.

[0045] E22 is the spherical agglomerates of embodiment E19 or E20, wherein the spherical agglomerates are characterized by thin flakes of primary particles associated in a sphere-like shape as observed in the scanning electron microscopy images of FIG. 1 , FIG. 2, FIG. 3, FIG. 5, FIG. 6, FIG. 7 or FIG. 8. E23 is the spherical agglomerates of any one of the embodiments E19 to E22, wherein the spherical agglomerates have a particle size distribution with a D[v, 0.5] count of about 50 microns to not more than about 250 microns and a D[v,0.9] count of about 100 microns to not more than about 500 microns.

[0046] E24 is the spherical agglomerates of embodiment E23 that have a particle size distribution with a D[v, 0.5] count of about 70 microns to not more than about 190 microns and a D[v, 0.9] count of about 155 microns to not more than about 370 microns.

[0047] E25 is the spherical agglomerates of any one of the embodiments E19 to E24, wherein the spherical agglomerates are characterized by thin flakes of primary particles associated together to form a sphere-like shape, wherein the flakes have a particle size distribution of about 10 to about 125 microns long by about 10 to about 125 microns wide and about 0.05 to about 1 micron thick.

[0048] E26 is the spherical agglomerates of embodiment E25 wherein the flake size distribution is about 15 to about 100 microns long by about 15 to about 100 microns wide and about 0.1 to about 1 micron thick.

[0049] E27 is the spherical agglomerates of embodiment E25 or E26, wherein the flake size distribution is about 35 to about 50 microns long by about 35 to about 50 microns wide and about 0.1 to about 1 micron thick.

[0050] Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined.

[0051] Definitions

[0052] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

[0053] As used herein, the term “about” when used to modify a numerically defined parameter (e.g., a D[v, 0.5] or D[v, 0.9] count or a particle size) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a a D[v, 0.5] count of about 50 microns means 50 microns ± 10%, i.e. , it may vary between 45 microns and 55 microns. “Optional" or "optionally" means that the subsequently described event or circumstance may, but need not occur, and the description includes instances where the event or circumstance occurs and instances in which it does not.

[0054] “D[v, 0.5]”, sometimes also referred to as “Dv50”, represents the volume median diameter in particle size distribution analysis. It indicates the particle size at which 50% of the sample's volume is composed of particles smaller than that size, and 50% is composed of particles larger. In simpler terms, it's the size that divides the particle size distribution into two equal halves by volume.

[0055] “D[v, 0.9]”, sometimes also referred to as “Dv90”, represents the volume-based 90thpercentile particle size in a particle size distribution. This means that 90% of the particles in the sample, by volume, are smaller than the size indicated by D[v, 0.9], In simpler terms, D[v, 0.9] indicates that 90% of the particles, by volume, are smaller than the size specified.

[0056] Spherical agglomerates can be recognized visually by those skilled in the art with techniques such as polarized light and scanning electron microscopy. Prior to this disclosure, spherical agglomerates of avibactam tomilopil were not known to exist, and it was not known how avibactam tomilopil spherical agglomerates could be successfully made.

[0057] The avibactam tomilopil spherical agglomerates of the present invention are uniquely characterized by thin flakes of primary particles associated in a sphere-like shape as observed using scanning electron microscopy imaging. Flakes or flakeshaped particles in the present invention refer to particles which are thin, flat and have a plate-like shape. They are characterised by a high diameter-to-thickness aspect ratio. In the case of the avibactam tomilopil spherical agglomerates of the present invention, the flake size ranges from about 15 to about 100 microns long and about 15 to about 100 microns wide with a thickness of less than about 1 micron and more than about 0.05 microns as described herein.

[0058] A neat reaction is a reaction that is run without solvent.

[0059] A telescoped reaction is a sequential one-pot synthesis with reagents added to a reactor one at a time and without work-up i.e, without steps taken after the chemical reaction to isolate and purify the product obtained. Hot filtration is a filtration method at higher temperature mainly used to separate solids from a hot solution. The upper temperature limit that can be used in hot filtration is the boiling point of the solvent being used.

[0060] The terms “concentrated”, “evaporated”, and “concentrated in vacuo" refer to the removal of solvent at reduced pressure on a rotary evaporator with a bath temperature less than about 60 °C (or at a temperature as specified) or using a short path distillation column with a collection vessel for the distillates.

[0061] The terms “room temperature” or “ambient temperature” mean a temperature between about 18 and about 25 °C.

[0062] Experimental Procedures

[0063] The following illustrate the process to synthesis spherical agglomerate particles of avibactam tomilopil. All starting materials in these Preparations and Examples are either commercially available or can be prepared by methods known in the art or as described herein (AVI-BU and IVb). Preparation of AVI-BU is carried out as discussed in Org. Process Res. Dev. 2016, 20, 1799-1805, starting with benzylbocglutamate through a telescoped process to provide the oxyamine oxalate. This oxyamine oxalate then undergoes an ammonolysis to provide an amide, which is then reacted through a piperidine protection, benzylhydroxylamine reaction and deprotection to provide the AVI-BU starting material. This starting material can be recrystallized with THF / water to ensure high purity material for the subsequent steps. Preparation of the compound of formula IVb is a Fischer esterification on hydroxypivalic acid with ethanol and sulfuric acid.

[0064] The processes of the invention may be carried out as described below and as depicted in Schemes 1 and 2.

[0065] All reactions were carried out using continuous stirring under an atmosphere of nitrogen or argon gas unless otherwise noted. When appropriate, reaction apparatuses were dried under dynamic vacuum using a heat gun, and anhydrous solvents (Sure- Seal™ products from Aldrich Chemical Company, Milwaukee, Wisconsin or DriSolv™ products from EMD Chemicals, Gibbstown, NJ) were employed. In some cases, commercial solvents were passed through columns packed with 4A molecular sieves, until the following QC standards for water were attained: a) <100 ppm for dichloromethane, toluene, / V, / V-dimethylformamide, and tetrahydrofuran; b) <180 ppm for methanol, ethanol, 1 ,4-dioxane, and diisopropylamine. For very sensitive reactions, solvents were further treated with metallic sodium, calcium hydride, or molecular sieves, and distilled just prior to use. Other commercial solvents and reagents were used without further purification. For syntheses referencing procedures in other Examples or Methods, reaction conditions (reaction time and temperature) may vary. Products were generally dried under vacuum before being carried on to further reactions.

[0066] Reaction progress can be monitored using liquid chromatography-mass spectrometry (LCMS), high-performance liquid chromatography (HPLC), and / or gas chromatography-mass spectrometry (GCMS) analyses. LCMS data can be acquired on an Waters Acquity instrument Acquity C18, Acquity Phenyl Hexyl, and Primsep 100, columns, aceton itrile / water gradients, and either trifluoroacetic acid, formic acid, or ammonium acetate modifiers. The column eluate is analyzed using a Waters SQD or QDa scanning in both positive and negative ion modes from 100 to 1200 Da. Other similar instruments can also be used. HPLC data were generally acquired on a Waters Acquity or Agilent 1200 Series instrument, using the columns indicated, acetonitrile / water gradients, and either trifluoroacetic acid or ammonium acetate modifiers. GCMS data are acquired using an Agilent Hewlett Packard 6890 oven with an HP 6890 injector, DB-624 column (12 m x 0.2 mm x 0.33 pm), and hydrogen or nitrogen carrier gas. The sample can be analyzed on an HP 5973 mass selective detector scanning from 50 to 550 Da using electron ionization. GCFID data are acquired using an Agilent Hewlett Packard 6890 oven with an HP 6890 injector, DB-624 column (25 m x 0.15 mm x 0.84 pm) or DB-Stabilwax column, and hydrogen or nitrogen carrier gas. Purifications are performed by medium performance liquid chromatography (MPLC) using Isco CombiFlash Companion, AnaLogix IntelliFlash 280, Biotage SP1 , or Biotage Isolera One instruments and pre-packed Isco RediSep or Biotage Snap silica cartridges. Chiral purifications were performed by chiral supercritical fluid chromatography (SFC), generally using Berger or Thar instruments; columns such as ChiralPAK-AD, -AS, -IC, Chiralcel-OD, or -OJ columns; and CO2 mixtures with methanol, ethanol, 2-propanol, or acetonitrile, alone or modified using trifluoroacetic acid or propan-2-amine. UV detection can be used to trigger fraction collection. For syntheses referencing procedures in other Examples or Methods, purifications may vary: in general, solvents and the solvent ratios used for eluents / gradients were chosen to provide appropriate RfS or retention times. Mass spectrometry data are reported from LCMS analyses. Mass spectrometry (MS) is performed via atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (El) or electron scatter ionization (ES) sources. Proton nuclear magnetic spectroscopy (1H NMR) chemical shifts are given in parts per million downfield from tetramethylsilane and were recorded on 300, 400, 500, or 600 MHz Varian, Broker, or Jeol spectrometers. Chemical shifts are expressed in parts per million (ppm, 6) referenced to the deuterated solvent residual peaks (chloroform, 7.26 ppm; CD2HOD, 3.31 ppm; acetonitrile-c , 1.94 ppm; dimethyl sulfoxide-c / 5, 2.50 ppm; DHO, 4.79 ppm). The peak shapes are described as follows: s, singlet; d, doublet; dd, doublet of doublet; ddd, doublet of doublet of doublet; dt, doublet of triplet; t, triplet; q, quartet; qd, quartet of doublet; quin, quintet; m, multiplet; br s, broad singlet; app, apparent. Analytical SFC data were generally acquired on a Berger analytical instrument as described above. Optical rotation data were acquired on a PerkinElmer model 343 polarimeter using a 1 dm cell. Microanalyses were performed by Quantitative Technologies Inc. and were within 0.4% of the calculated values.

[0067] Unless otherwise noted, chemical reactions were performed at room temperature (i.e. , between about 18°C and 25°C, preferably at about 23°C). Unless noted otherwise, all reactants were obtained commercially and used without further purification or were prepared using methods known in the literature.

[0068] For convenience, well known abbreviations are used herein including: “ACN" (acetonitrile); “°C” is (degrees Celsius); “CDI” (T-Carbonyldiimidazole); “CLLE” (continuous liquid-liquid extraction); “CO2” (carbon dioxide); “DABCO” (1 ,4 diazabicyclo[2.2.2.]octane); “DBU” (1 ,8-Diazabicyclo[5.4.0]undec-7-ene); “DIPEA” (N,N- Diisopropylethylamine); “DMF” (dimethylformamide); “DMSO-de” (hexadeutero dimethylsulfoxide); “eq.” or “equiv.” (equivalents); “EtOAc” (ethyl acetate); “EtOH” (ethanol); “FMOC-CI” (Fluorenylmethyloxycarbonyl chloride); “g” (gram); “GCMS” (gas chromatography-mass spectrometry); “h” or “hr” or “hrs” (hours); “HCI” (hydrogen chloride); “HPLC” (high-performance liquid chromatography); “HRMS” (high resolution mass spectroscopy); “Hz” (hertz); “IPA” (isopropyl alcohol); “iPrOAc” (isopropyl acetate); “iPrOH” (isopropanol); “K” (Kelvin); KF (Karl Fisher); “kg” (kilogram); “K-OTf” (potassium triflate); “K-PFe” (potassium hexafluorophosphate); “L” (liter); “M” (mole or molar); “LCMS” (liquid chromatography-mass spectrometry); “mbar” (millibar); “MeCN” (acetonitrile); “MEK” (methyl ethyl ketone); “MeOH” (methanol); “MeTHF” (2- methyltetrahydrofuran); “MgCI (magnesium chloride); “mg” (milligram); “pg” (microgram); “MHz” (megahertz); “min” (minutes); “mL” (milliliter); “p.L” (microliter); “mm” (millimeter); “mmol” (millimole); “pm”(micrometer or micron); “pmol” (micromole);

[0069] “MTBD” (7-methyl-1 ,5,7, triazabicyclo(4.4.0)dec-5-ene ); “MTBE” or “MtBE” (methyl tertbutyl ether); “NaBF4” (sodium tetrafluoroborate); “NaCI” (sodium chloride); “NaHCOs” (sodium bicarbonate); “NaOH” (sodium hydroxide); “Na2SO4” (sodium sulfate);

[0070] “NH4OAc” (ammonium acetate); “NLT” (not less than); “NMT” (not more than); “PFR” (plug flow reactor); “PBR” (packed bed reactor); “psig” (pounds per square inch gauge pressure); “Pd(OAc)2” (palladium acetate); “PdCI (palladium chloride); “Pd(dba)s” (tris(dibenzylideneacetone)dipalladium(O)); “Pd / C” (palladium on carbon); “Pd / AI” (palladium on alumina); “PSD” (particle size distribution); “PXRD” (powder x-ray diffraction); “QTOF” (Quadrupole Time-of-Flight); “rpm” (round per minute); “SFC” (supercritical fluid chromatography); “TBD” (triazabicyclodecene); “THF” (tetrahydrofuran); “Tj” (jacket temperature); “TLC” (thin-layer chromatography);

[0071] “TMEDA” (tetramethylethylenediamine); “TMG” (1 ,1 ,3,3-tetramethylguanidine); “Tr” (reactor temperature); “LIPLC” (ultra-performance liquid chromatography); “v” (volume); “wrt” (with respect to) and “wt” (weight).

[0072] Hydrogenation may be performed in a Parr shaker or other agitated reactor under pressurized hydrogen gas, or in a packed bed gas-liquid flow hydrogenation reactor apparatus under hydrogen pressure and at specified temperature or as otherwise specified.

[0073] HPLC, LIPLC, LCMS, GCMS, and SFC retention times are measured using the methods noted in the procedures.

[0074] The optical rotation of an enantiomer can be measured using a polarimeter. According to its observed rotation data (or its specific rotation data), an enantiomer with a clockwise rotation was designated as the (+)-enantiomer and an enantiomer with a counter-clockwise rotation was designated as the (-)-enantiomer. Racemic compounds are indicated either by the absence of drawn or described stereochemistry, or by the presence of (+ / -) adjacent to the structure; in this latter case, the indicated stereochemistry represents just one of the two enantiomers that make up the racemic mixture.

[0075] The compounds and intermediates described below were named using the naming convention provided with ACD / ChemSketch 2019.1.1 , File Version C05H41 , Build 110712 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada) or using the structure naming function in ChemDraw 18.0 (PerkinElmer® Informatics; perkinelmer.com). The naming convention provided with ACD / ChemSketch 2019.1.1 or ChemDraw 18.0 is well known by those skilled in the art and it is believed that the naming convention provided with ACD / ChemSketch 2019.1.1 generally comports with the IIIPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules.

[0076] Solid Form Data provided herein was obtained using the following Powder X-Ray Diffraction (PXRD) Method: The powder X-ray diffraction analysis was conducted using a Bruker AXS D8 Advance diffractometer equipped with a copper (Cu) radiation source. The divergence slit was set at 10 mm continuous illumination. Diffracted radiation was detected by a PSD-Lynx Eye detector, with the detector PSD opening set at 4.1 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. Data was collected in the Theta-Theta goniometer at the Cu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of 0.02 degrees and a step time of 0.3 second. The anti-scatter screen was set to a fixed distance of 31.5 mm. Samples were rotated at 15 / min during collection. Samples were prepared by placing them in a silicon low background sample holder and rotated during collection. Data was collected using Bruker DIFFRAC Plus software and analysis was performed by EVA diffract plus software. The PXRD data file was not processed prior to peak searching. Using the peak search algorithm in the EVA software, peaks selected with a threshold value of 1 were used to make preliminary peak assignments. To ensure validity, adjustments were manually made; the output of automated assignments was visually checked, and peak positions were adjusted to the peak maximum. Peaks with relative intensity of > 3% were generally chosen. Typically, the peaks which were not resolved or were consistent with noise were not selected. A typical error associated with the peak position from PXRD stated in USP up to ± 0.2° 2-theta (USP-941 ). Unless stated otherwise the variance for each peak reported in the PXRD peak tables is + / - 0.2° 2-theta.

[0077] Scheme 1 Step 1 Step 2 i. FMOC-CI, DIPEA, chlorobenzene

[0078] The route to manufacture avibactam tomilopil begins from building blocks already disclosed in the chemical literature. From Scheme 1 above, Steps 1 and 2 are disclosed in Org. Process Res. Dev. 2016, 20, 1799-1805. The first step is an ammonolysis of the compound of formula AVI-00 to provide the amide of formula AVI- amide. The second step employs a protection / benzylhydroxylamine reaction with CDI / deprotection scheme to allow for the benzoxuramide urea formation giving AVI-BU.

[0079] Step 5

[0080] Step 3 AVP

[0081] Scheme 2 begins with the product AVI-BU as obtained from Scheme 1 and a recrystallization with hot filtration to remove insoluble byproducts from Step 2 is employed (Step 2R) for the manufacture of avibactam tomilopil to ensure those insoluble byproducts do not impact processing in later steps.

[0082] Next, avibactam tomilopil is produced via two different processes for the telescoped sequence of Step 3 and Step 5. As shown in Scheme 2, the bond-forming for these processes is the same: AVI-BU is debenzylated and subsequently coupled with the chlorosulfate of formula IVb made in Step 4. There is no isolation of the debenzylated product of formula III obtained in Step 3. The key difference between the Flow process and the Batch process is that the Flow process utilizes continuous processing for the reaction and extractive workup steps while the Batch process is processed fully in batch mode. In addition, the process solvents and base employed in both steps, and the debenzylation methods are different between the two processes (further details provided in Examples herein). The product from either Step 3 / 5 sequence is labeled as “crude AVP”.

[0083] The Batch process (“Batch”) is performed in batch mode and focuses on telescoping the two bond forming steps together, eliminating the need to isolate the high thermally hazardous intermediate of formula III and using a stabilizing agent (sodium triflate) to ensure that the chlorosulfate addition occurs at a high yield (at least 75% across two steps). Solvent and reagent choice is key to ensure the process is scalable. The use of a transfer hydrogenation for the debenzylation step provided the cleanest method to telescope into the chlorosulfate addition, which was extremely sensitive to solvents and reagents use upstream.

[0084] The Flow process (“Flow”) is performed in continuous mode, also allowing for telescoping through the thermally hazardous intermediate of formula III and providing process safety through flow. At any given time the reaction volume of this process is low, which translates to a low thermal potential and lower consequences should decomposition temperatures be reached. Flow processing allows for tight control on stoichiometry, which in this process ensured the chlorosulfate addition proceeded in good yield. Solvents and processing were employed in both the crude AVP isolation and final AVP isolation to form spherical agglomerates, providing a more scale-friendly sized material for filtration and isolation. Step 5R can be run using the same crude AVP from either the Batch or Flow process. Step 5R is a recrystallization step with an aqueous workup to provide further purification. AVP is isolated as spherical agglomerates, to ensure ease of processing and consistent properties. For AVP, the use of 2-methyltetrahydrofuran, isopropyl acetate, tetrahydrofuran, ethyl acetate, and methyl ethyl ketone as solvent with heptane, hexane or cyclohexane as antisolvent ensures formation of the spherical agglomerates of the present invention. Materials

[0085] Preparation 1 : Step 2R, Recrystallization of Avibactam Benzoxuramide (AVI-BU)

[0086] Avibactam Benzoxuramide Avibactam Benzoxuramide AVI-BU AVI-BU

[0087] To a Vessel A equipped with agitator, condenser and temperature control is charged tetrahydrofuran (13.29 g, 1.5 ml / g) and water (20.00 g, 2.0 ml / g) at Tj = 20 - 25 °C and stirred. Crude AVI-BU (10.0 g, 1.0 eq.) and Celite (0.75 g, 0.075 g / g) are charged and rinsed with tetrahydrofuran (4.43 g, 0.5 ml / g). The mixture was heated to 50 - 60 °C and kept for a minimum of 60 minutes for dissolution. To remove polymeric insolubles, the hot mixture was passed through a submicron filter (pore size <t> < 1 pm) into a clean Vessel B. Vessel A and filter is rinsed forward to Vessel B with premixed solution of tetrahydrofuran (2.66 g, 0.3 ml / g) and water (3.00 g, 0.3 ml / g). Once Vessel B contents are at Tr = 50 - 60 °C with, water (70.00 g, 7.0 ml / g) is dosed rapidly with vigorous stirring, while keeping Tr not less than 45 °C. The slurry is then cooled down to 10°C at 0.5 °C / min and filtered. The filter cake is rinsed with a premixed solution of tetrahydrofuran (3.54 g, 0.4 ml / g) and water (16 g, 1.6 ml / g) and dried at 50 °C under vacuum to achieve a yield of about 90% recrystallized avibactam benzoxuramide (AVI-BU).1H NMR (400 MHz, CD3CN) 5 7.52 - 7.32 (m, 5H), 6.62 (s, 1 H), 5.99 (s, 1 H), 4.93 (dd, J = 28.0, 5.2 Hz, 2H), 3.78 (d, J = 7.7 Hz, 1 H), 3.56 (td, J = 3.5, 2.0 Hz, 1 H), 2.99 (dddd, J = 11 .8, 5.0, 2.4, 1.1 Hz, 1 H), 2.82 (d, J = 11.8 Hz, 1 H), 2.26 - 2.16 (m, 1 H), 1.94 - 1.87 (m, 1 H), 1.83 - 1.68 (m, 1 H), 1.67 - 1.54 (m, 1 H).13C NMR (101 MHz, CD3CN) 5 172.70, 168.32, 137.03, 130.19, 129.50, 129.37, 78.40, 61.10, 58.20, 48.37, 21.52, 18.52.

[0088] Other known reaction conditions for Preparation 1 include solvent composition (tetrahydrofuran to water ratio), which is known to have an impact on solubility of AVI- BU. Dissolution temperature may change depending on the solvent composition and volume. Changes to solvent ratio and volume during dissolution may result in changes to overall process volume and yield. Larger pore-size filters (average pore size > 1 pm) may result in incomplete polymeric insoluble removal during hot filtration.

[0089] Preparation 2: Step 4, Synthesis of Intermediate IVb e

[0090] To a jacket reactor at 15 °C was charged sulfuryl chloride (1.0 eq., 500 g) with overhead stirring and nitrogen sweep through a condenser to a scrubber filled with 20% NaOH in water. Stirring was set to 400 rpm and care was taken to shield the reactor from light. The compound of formula IVa (1 .02 eq., 513 g) was added dropwise over 6 hours. After addition, a subsurface nitrogen sparge was maintained for 21 hours to remove residual HCI to provide the compound of formula IVb (838 g) in 95% yield as a clear, colorless oil.1H NMR (400 MHz, CDCI3, 298K): 4.52 (s, 2H), 4.18 (q, J = 7.8 Hz, 2H), 1.30 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H).13C NMR (100 MHz, CDCI3, 298K): 173.01 , 82.02, 61.60, 41.62, 20.97, 13.03.

[0091] The synthesis of the compound of formula IVb can also be performed as a continuous reaction, specifically to feed the continuous process for Step 3 / 5 in Example 2. This can be done as a neat (no solvent) process or as base-mediated process in solvent. For the neat process, the chlorosulfate reaction is run in a plug flow reactor, combining the compound of formula IVa and sulfuryl chloride streams through a mixing tee at 25°C for a residence time between 3 to 10 min under at least 20 psig (about 1 .38 bar) backpressure. For the base-mediated process, the compound of formula IVa in acetonitrile is combined inside a plug flow reactor with a neat stream of sulfuryl chloride, followed by the combined IVa / sulfuryl chloride stream being mixed with 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile. Temperatures and residence times varied between -40 to 0°C and 2 to 3 min.

[0092] Examples

[0093] Step 3 Step 5 i.DABCO NaOTf water MEK

[0094] IVb

[0095] To a jacketed reactor at 20 °C was charged the compound of formula AVI-BU (1.0 equiv, 40 g), followed by 5 wt% Pd / alumina (0.10 g / g, 4 g) and methyl ethyl ketone (4.75 ml / g, 190 ml). The internal temperature and set to 15 °C and while stirring, a solution of 1 ,4 diazabicyclo[2.2.2.]octane (DABCO, 0.1 equiv, 1.63 g) and formic acid (1.3 equiv, 8.692 g) in methyl ethyl ketone (1 ml / g, 40 ml) was added maintaining the internal temperature between 10 - 20 °C. This mixture was held at 15 °C for NLT 24 hours until AVI-BU NMT 2% and formic acid content is NMT 0.25%. To this slurry held at 0 °C was charged a solution of DABCO (1 .2 equiv, 19.96 g) in methyl ethyl ketone (6 ml / g, 240 ml), followed by sodium trifluromethylsulfonate (0.4 equiv, 10.2 g) and water (0.2 ml / g, 8 g). This was followed by a linear dose of the compound of formula IVb (1.1 equiv, 39.11 g) over 6 hours maintaining the internal reactor temperature at 0 °C. The mixture was agitated for NLT 4 hours till the compound of formula III content was NMT 5%. The slurry was filtered to remove all the solids and the cake was washed twice with isopropyl acetate (4 ml / g, 160 ml). Heptane (4 ml / g, 160 ml) was added to the filtrate as a wash co-solvent to improve phase splits. The obtained filtrate was washed at room temperature with water (4 ml / g, 160 ml), followed by two 5% brine washes (4 ml / g, 160 ml each and a final water wash (4 ml / g, 160 ml). The washed organic layer is then concentrated using vacuum and internal temperature NMT 35 °C to 7 ml / g until the water content by KF NMT 0.5%. The product was crystallized by adding additional isopropyl acetate (3 ml / g, 120 ml) and heptane (11 ml / g, 440 ml) at 35 °C over an hour and the slurry was cooled down to 10 °C and granulated for 1 hour before filtering and washing twice with a mixture of heptane and isopropyl acetate (2.5:0.5 ml / g, 100 ml:20 ml) and drying under vacuum at room temperature to give the crude AVP (57.16 g) in 75 - 85% yield.1H NMR (400 MHz, CD3CN) 5 6.61 (s, 1 H), 6.01 (s, 1 H), 4.67 (d, J = 9.2 Hz, 1 H), 4.54 (d, J = 9.1 Hz, 1 H), 4.13 (q, 2H), 4.11 (d, J = 6.0 Hz, 1 H), 3.99 (d, J = 6.7 Hz, 1 H), 3.25 (d, J = 12.1 Hz, 1 H), 3.09 (d, J = 12.3 Hz, 1 H), 2.31 - 2.17 (m, 1 H), 2.10 - 1.99 (m, 1 H), 1.90 - 1.74 (m, 2H), 1.23 (s, 6H), 1.22 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, CD3CN) 5 174.58, 171.37, 168.45, 81.32, 62.31 , 61.60, 61.26, 47.03, 43.21 , 21.76, 21.41 , 20.92, 18.59, 13.96. HRMS (ESI) m / z calcd for C14H23N3O8S [M + H]+: 394.12; found 394.1271.

[0096] For the step 3 debenzylation reaction, other solid supported heterogenous catalysts like palladium on carbon (Pd / C) may be used with hydrogen donors like triethylsilane in isopropanol for debenzylation. Different formate salts like potassium, ammonium and amine formates perform well with palladium on alumina (Pd / AI) in solvent systems consisting of acetone, methyl ethyl ketone or isopropanol.

[0097] For step 5 chlorosulfate coupling, bases like 1 ,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine and tetramethylethylenediamine (TMEDA) performed well in aprotic solvents like acetone or methyl ethyl ketone. Bases such as 1 ,1 ,3,3- tetramethylguanidine (TMG), Diazabicyclo[5.4.0]undec-7-ene (DBU) and triazabicyclo(4.4.0)dec-5-ene (MTBD) can be used for the step 5 coupling in protic solvents. To stabilize the compound of formula IVb, halide scavengers like potassium or sodium triflate (K / Na-OTf), potassium or sodium hexafluorophosphate (K / Na-PFe), sodium tetrafluoroborate (NaBF4) can be used with DABCO in methyl ethyl ketone for step 5 coupling.

[0098] Example 2: Step 3 / 5, Synthesis of crude Avibactam Tomilopil (Flow process) Step 3 Step 5

[0099] IVb

[0100] The first chemical step (step 3) is a debenzylation reaction of the compound of formula AVI-BU (1.0 eq, 1 kg) dissolved in acetonitrile (ACN, 15 L / kg, 15 L) and isopropyl alcohol (IPA, 10 L / kg, 10 L) and was run through a packed bed of carbon. The carbon- treated feed stream was then combined with hydrogen gas (9.4 eq) and fed through a packed bed reactor (gas-liquid flow reactor) at 25-30°C. This yields a non-isolated intermediate of formula III and toluene as a by-product. The III product solution is then degassed, followed by being pumped into the step 5 reactor, which is a plug flow reactor (PFR). The intermediate of formula III (1.0 eq., 672.6 g) is first combined with 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 1.4 eq., 0.77 kg) dissolved in acetonitrile (2.1 L / kg, 2.1 L) after which these two streams are mixed and spend a relatively short amount of residence time together (1 second) before mixing with the compound of formula IVb (1 .4 eq., 1 .24 kg). Once all three streams are mixed, they flow into the main part of the reactor where they react for 1 min of residence time at 10°C. The outlet of the PFR is fed directly into the first continuous liquid-liquid extraction (CLLE) unit to perform the first extraction in the presence of additional isopropyl acetate (1 :1 v / v wrt process, 30.0 L) and 10 wt% MgCl2 (1 :1 v / v wrt process, 30.0 L). The CLLE performs both the extraction as well as the phase separation, where the aqueous outlet is sent to waste and the organic solution containing the product is first collected into a small receiving vessel, followed by being pumped into the second CLLE unit where it is washed with 10 wt% MgCl2 (1 :1 v / v wrt process, 27.6 L). The aqueous stream is again discarded to waste and the organic stream containing the product is collected in a receiving vessel. After being washed with 10 wt% MgCl2 in the second CLLE unit, the organic phase containing the product undergoes two more identical water washes in batch mode (0.5:1 v / v wrt process, 21.6 L each), before pumping all the organic phase (after phase split) over to a second batch vessel. Within this batch vessel, the product solution is distilled under vacuum down to 10 L / kg (1.0 L) wrt the compound of formula AVI-BU (8 L / kg wrt crude AVP) with a jacket temperature NMT 40°C. Upon completing the distillation, the reaction solution is cooled to 15°C, followed by adding heptane (1.5:1 v / v wrt process, 12.0 L) over no less than 3 hr to perform an anti-solvent crystallization. The product slurry is then pumped out of the vessel, followed by filtration, cake washing (4 L / kg, 4.0 L) and drying at ambient temperature, yielding the crude isolated product of step 5 resulting in -70% overall yield.1H NMR (400 MHz, CD3CN) 5 6.61 (s, 1 H), 6.04 (s, 1 H), 4.67 (d, J = 9.1 Hz, 1 H), 4.54 (d, J = 9.1 Hz, 1 H), 4.13 (q, J = 7.0 Hz, 2H), 4.11 (d, J = 5.8 Hz, 1 H), 3.99 (d, J = 6.8 Hz, 1 H), 3.25 (d, J = 12.1 Hz, 1 H), 3.09 (d, J = 12.3 Hz, 1 H), 2.33 - 2.17 (m, 1 H), 2.06 (dq, J = 7.8, 2.7 Hz, 1 H), 1.91 - 1.76 (m, 2H), 1.23 (s, 6H), 1.22 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, CD3CN) 5 174.95, 171.75, 168.82, 81.69, 62.68, 61.97, 61.63, 47.39, 43.58, 22.13, 21.78, 21.28, 18.96, 14.33. HRMS data (QTOF in positive mode using an NH4OAC method): Proposed formula: Ci4H24N30sS+with exact mass = 394.128; actual mass found [M+H]+= 394.1274, accurate to within 2 ppm.

[0101] The telescoped reaction sequence above can also be run using DMF / IPA instead of ACN / IPA as the solvent system. Other bases that can be used include 1 ,1 ,3,3- tetramethylguanidine (TMG), 1 ,4 diazabicyclo[2.2.2.]octane (DABCO), 7-methyl-1 ,5,7, triazabicyclo(4.4.0)dec-5-ene (MTBD), and triazabicyclodecene (TBD). Step 3 may also be carried out as a transfer hydrogenation flowing through a packed bed reactor, rather than using hydrogen gas as the H2 source. The catalyst can be supported by either carbon or alumina. The extraction can be performed using pure water, magnesium chloride (MgCk), calcium chloride (CaCk), lithium chloride (LiCI), or sodium chloride (NaCI) using between 1 -4 washes. For the isolation of crude AVP, methylcyclohexane and toluene can be used as anti-solvents in place of heptane.

[0102] Example 3: Steps 3 & 5: Synthesis of Avibactam Tomilopil (Batch process) Step 3

[0103] Step 5 i. DBU, IPA, EtOAc

[0104] IVb

[0105] To vessel A was added ethanol (160 kg), THF (360 kg) and the compound of formula AVI-BU (67 kg) at 25 °C. The addition funnel was rinsed with THF (30 kg). After the mixture was cooled to 5 °C, 10% Pd / C (12.6 kg) and water (1 .2 kg) were charged, and the reaction placed under a hydrogen blanket (0.6 MPa). Upon reaction completion the mixture was filtered, and vessel A rinsed twice with a mixture of ethanol (16 kg) and THF (36 kg). The filtrate in vessel B was cooled to -10 °C, diluted with water (27 kg) and crystallized with MTBE (596 kg) then heptane (364 kg). The slurry was filtered and washed twice with MTBE (75 kg). The solids were dried to afford the compound of formula lll-monohydrate (i.e., the monohydrate of the compound of formula III) as a white crystalline solid (40.4 kg, 80% yield).

[0106] To vessel C was charged isopropanol (375 kg), ethyl acetate (180 kg), the compound of formula lll-monohydrate (39.4 kg) and the compound of formula IV-b (71.2 kg), at - 25 °C. DBU (44.3 kg) was added to the mixture over 6 hr maintaining temperature at - 30 to -20 °C. After 8 hr the mixture was treated with water (788 kg) and warmed to 20 °C. The mixture was diluted with ethyl acetate (540 kg) and the layers were settled. The bottom layer was discarded, and the organic layer washed four times with water (394 kg, 394 kg, 197 kg, 197 kg). The organic layer was concentrated to 355-433 L then crystallized with heptane (539 kg) at 20 °C. The slurry was filtered and washed twice with heptane (54 kg). The solids were dried to afford crude AVP as a white solid (44.15 kg, 57%). Example 4: Step 5R, Recrystallization of Avibactam Tomilopil crude AVP 85% Yield

[0107] To the jacketed reactor of 1 L capacity at 25°C was charged crude AVP (1 .0 equiv.

[0108] 114.4 mmol, 45 g), followed by 2-methyl tetrahydrofuran (9.0 mL / g, 405 mL), methyl tert-butyl ether (1.0 mL / g, 45 mL), and water (4.0 mL / g, 180 mL). Tj was set to 30°C over 10 min and then Tr was set to 30°C over 10 min. the reaction mixture was stirred for 10 min and the two phases were allowed to separate. The heavier phase was decanted. This water wash was repeated two times (4.0 mL / g, 180 mL each). At the end of wash step, the organic phase was retained. KF for ingoing organic phase was measured. 2-Methyl tetrahydrofuran (6.5 mL / g, 293 ml) was charged and a distillation at 100 mbar and Tj-Tr= 10 °C was performed. The maximum Tj temperature should not exceed to 40 °C. Distillation to 6.5 mL / g (~300 mL) was performed. The temperature was cooled down to 20 °C, the vacuum broken and dry 2-methyl tetrahydrofuran (6.5 mL / g, 293 ml) was charged. Distillation to 6.5 mL / g was repeated under vacuum two times to ensure KF reached NMT 0.3%. The maximum Tj temperature should not exceed to 40 °C. Once KF target was met, the solution was cooled to 30 °C over 15 minutes. The stirring speed was set to 234 rpm and the baffle was inserted. The solution was further cooled to 25 °C over 10 min. AVP seeds (0.5wt% wrt. AVP, 225 mg) were added. Wait for 30 min and ensure seed holds. n-Heptane (15.2 mL / g, 684 mL) was charged over 3 h. The slurry was hold at 25 °C for NLT 1 hr. The slurry was cooled to 10 °C over 1 hr. The slurry was granulated for NLT 2 h. Filtration and wash with 2 V (2-MeTHF: Heptane, 30:70 v / v, premixed solvent combination) was performed. Solids were dried at room temperature to get the compound of formula AVP at typical yield of 85-90%.1H NMR (600 MHz, DMSO-de, 298K):1H NMR (400 MHz, DMSO) 5 7.54 (s, 1 H), 7.39 (s, 1 H), 4.64 (d, J = 9.1 Hz, 1 H), 4.54 (d, J = 9.1 Hz, 1 H), 4.11 (q, J = 6.9 Hz, 2H), 4.09 (d, 1 H), 3.92 (dd, J = 7.6, 2.1 Hz, 1 H), 3.19 (s, 2H), 2.11 (ddt, J = 14.7, 6.9, 2.2 Hz, 1 H), 2.00 - 1.90 (m, 1 H), 1.91 - 1.78 (m,1H), 1.73 (ddt, J = 14.8, 10.0, 7.3 Hz, 1 H), 1.19 (s, 6H), 1.18 (t, J = 7.1 Hz, 3H).13C NMR (150 MHz, DMSO-de, 298K):13C NMR (101 MHz, CD3CN) 6 174.95, 171.75, 168.83, 81.70, 62.69, 61.97, 61.63, 47.40, 43.59, 22.14, 21.79, 21.29, 18.97, 14.34.

[0109] Final agglomerate formation is sensitive to water content of crystallization solvent system. Water content above 0.5 wt% results in more fines generation and shift in peak in PXRD to left. The stirring speed is also important in order to ensure agglomerates remain intact. At higher stirring speed agglomerates fall apart (200-500 rpm on 50- 100mL scale is acceptable but above that particles fall apart). Seeding is not exactly needed to initiate precipitation as particles are formed from oil droplets but seeding helped to get smaller particle size distribution (PSD).

Claims

CLAIMS1 . A process for preparing avibactam tomilopil comprising debenzylating AVI-BU of formula:AVI-BU though a transfer hydrogenation reaction in the presence of a palladium catalyst, a hydrogen donor, and a solvent to obtain the compound of formula III:followed by coupling of the compound of formula III with the compound of formula IVb:IVb in the presence of a base and a halide scavenger; wherein the compound of formula III is never isolated.

2. The process of claim 1 wherein the hydrogen donor is selected from the group consisting of formic acid, potassium formate, ammonium formate, amine formate, and triethylsilane; wherein the solvent is acetone, methyl ethyl ketone, isopropanol, or mixtures thereof; and wherein the palladium catalyst is on a solid support of alumina or carbon; or the palladium catalyst is selected from Pd(OAc)2, PdCl2, and Pd(dba)s.

3. The process of claim 1 or 2 wherein the base is selected from 1 ,4 diazabicyclo[2.2.2.]octane (DABCO), quinuclidine and tetramethylethylenediamine (TMEDA); and wherein the solvent is selected from acetone and methyl ethyl ketone.

4. The process of claim 1 or 2 wherein the base is selected from 1 , 1 ,3,3- tetramethylguanidine (TMG), 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), and 7-methyl- 1 ,5,7, triazabicyclo(4.4.0)dec-5-ene (MTBD); and wherein the solvent is isopropanol.

5. The process of any one of claims 1 to 4 wherein the halide scavenger is selected from the group consisting of potassium triflate (K-OTf), sodium triflate (Na-OTf), potassium hexafluorophosphate (K-PFe), sodium hexafluorophosphate (Na-PFe), and sodium tetrafluoroborate (NaBF4).

6. The process of claim 1 wherein the palladium catalyst is on a solid support of alumina, the hydrogen donor is formic acid, the base is 1 ,4 diazabicyclo[2.2.2.]octane, the solvent is methyl ethyl ketone, and wherein the halide scavenger is sodium triflate (Na-OTf).

7. A process for preparing avibactam tomilopil comprising debenzylating the compound of formula AVI-BU through a hydrogenation reaction in a packed bed gas-liquid flow reactor packed in the presence of a heterogeneous catalyst, a hydrogen source, and a solvent to obtain the compound of formula III, followed by coupling of the compound of formula III with a compound of formula IVb in a plug flow reactor in the presence of a base; wherein the compound of formula IVb is introduced into the reactor as a stream that is neat or synthesized continuously; and wherein the compound of formula III is never isolated.

8. The process of claim 7 wherein the solvent is a mixture of acetonitrile and isopropanol or a mixture of dimethylformamide and isopropanol; wherein the catalyst is palladium supported on carbon or alumina solid supports; wherein the hydrogen source is hydrogen gas or triethylsilane, and wherein the base is 1 ,8-Diazabicyclo[5.4.0]undec- 7-ene (DBU), 1 ,1 ,3,3-tetramethylguanidine (TMG), 7-methyl-1 ,5,7- triazabicyclo(4.4.0)dec-5-ene (MTBD), or triazabicyclodecene (TBD).

9. The process of claim 8, wherein the solvent is a mixture of acetonitrile and isopropanol, the catalyst is palladium supported on carbon, the hydrogen source is hydrogen gas, and the base is 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

10. A process for preparing avibactam tomilopil comprising the steps (a)-(c):(a) debenzylating the compound of formula AVI-BU by reacting it with hydrogen gas in the presence of a palladium on carbon heterogeneous catalyst to obtain the compound of formula III;(b) isolating the compound of formula III as a monohydrate with water, methyl tert-butyl ether (MTBE), and n-heptane; and(c) coupling the monohydrate compound of formula III obtained in step (b) with the compound of formula IVb in the presence of 1 ,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) in isopropanol and water.11 . The process of any one of claims 1 to 10 wherein avibactam tomilopil is subsequently crystallized by dissolving avibactam tomilopil in isopropyl acetate or 2- methyl tetrahydrofuran; optionally performing an aqueous work up followed by distilling off residual water; and isolating avibactam tomilopil with heptane.

12. The process of claim 11 wherein avibactam tomilopil is further recrystallized by dissolving avibactam tomilopil in 2-methyl tetrahydrofuran, methyl tert-butyl ether (MTBE), and water; performing an aqueous work up; distilling methyl tert-butyl ether (MTBE) and water off such that water is at a level of less than about 0.3% w / w water; and isolating avibactam tomilopil with heptane.

13. Avibactam tomilopil spherical agglomerates obtainable by the process according to any one of claims 1 to 12.

14. Avibactam tomilopil in the form of spherical agglomerates.

15. The spherical agglomerates of claim 13 or 14, wherein the spherical agglomerates have a particle size distribution with a D[v, 0.5] count of about 50 microns to not more than about 250 microns and a D[v,0.9] count of about 100 microns to not more than about 500 microns, and preferably a particle size distribution with a D[v, 0.5] count of about 70 microns to not more than about 190 microns and a D[v, 0.9] count of about 155 microns to not more than about 370 microns.

16. The spherical agglomerates of any one of claims 13 to 15, wherein the spherical agglomerates are characterized by thin flakes of primary particles associated together to form a sphere-like shape, wherein the flakes have a particle size distribution of about 10 to about 125 microns long by about 10 to about 125 microns wide and about 0.05 to about 1 micron thick, preferably of about 15 to about 100 microns long by about 15 toabout 100 microns wide and about 0.1 to about 1 micron thick and more preferably of about 35 to about 50 microns long by about 35 to about 50 microns wide and about 0.1 to about 1 micron thick.

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