Preparation method of intermediate for preparing (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfate)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Abstract

The present invention relates to the preparation of protected piperidine carboxylates suitable as intermediates for preparing the beta-lactamase inhibitor (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfato)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide via a series of further process steps including the sulfation of a hydroxyurea compound.

Description

Field of the Invention

[0001] The present invention relates to the preparation of piperidine carboxylates which are suitable as intermediates for preparing the beta-lactamase inhibitor (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide via a series of further process steps. This compound is β -lactamases and can be used as an effective treatment for bacterial infections when used in combination with β-lactam antibiotics. It would be desirable to develop a short, scalable and cost-effective synthetic route to such compounds.

[0002] One aspect of the present invention relates to protected piperidine carboxylates, including the preparation of tert-butyl 4-((2S,5S)-1-((nitrophenyl)sulfonyl)-5-(((nitrophenyl)sulfonyl)oxy)piperidine-2-carboxamido)piperidine-1-carboxylate. Another aspect of the present invention relates to the preparation of protected piperidine carboxylates, including tert-butyl 4-((2S,5S)-1-((nitrophenyl)sulfonyl)-5-(((nitrophenyl)sulfonyl)oxy)piperidine-2-carboxamido)piperidine-1-carboxylate. R ,2 S ,5 R The invention relates to a surprising and unexpected improvement in the sulfation of tert-butyl 6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate, which is an additional process step in the preparation of the β-lactamase inhibitor (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfato)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. Background of the Invention

[0004] Certain 7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamides are β -lactamase inhibitors and in combination with β -lactam antibiotics are effective in treating bacterial infections when used in combination. See, for example, U.S. Pat. No. 8,487,093, which discloses 7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamides, such as (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfate)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide and the synthesis of the compound from a ketosulfoxonium ylide intermediate containing an amide side chain, wherein the ylide intermediate is cyclized to 5-oxo-piperidine-2-carboxamide using an Ir, Rh or Ru catalyst.

[0005] U.S. Pat. No. 9,604,985 discloses a method for preparing N-protected 6-(piperidin-4-ylcarbamoyl)piperidin-3-yl sulfonate, which comprises contacting a (2S,5S)-5-hydroxypiperidine-2-carboxylic acid derivative with a protecting group agent such as 2-nitrobenzene-1-sulfonyl chloride in the presence of an aqueous base to form a lactone. The lactone is further contacted with an azacycloalkylamine and then with a sulfonyl halide in the presence of a tertiary amine base.

[0006] US 9,604,985 specifically exemplifies a complex four-step process for preparing the intermediate tert-butyl 4-((2S,5S)-1-((2-nitrophenyl)sulfonyl)-5-(((2-nitrophenyl)sulfonyl)oxy)piperidine-2-carboxamido)piperidine-1-carboxylate

[0007]

[0008] The method is to react (2S,5S)-5-hydroxypiperidine-2-carboxylic acid with 2-nitrobenzenesulfonyl chloride in the presence of trimethylamine to form the lactone (1S,4S)-5-((2-nitrophenyl)sulfonyl)-2-oxa-5-azabicyclo[2.2.2]octan-3-one. The lactone is then contacted with an azacycloalkylamine having a protecting group, such as Boc (tert-butyloxycarbonyl). The reaction product is then contacted with a sulfonyl halide in the presence of 4-dimethylaminopyridine to form tert-butyl 4-((2S,5S)-1-((2-nitrophenyl)sulfonyl)-5-(((2-nitrophenyl)sulfonyl)oxy)piperidine-2-carboxamido)piperidine-1-carboxylate.

[0009] Additional embodiments disclosed in US 9,604,985 add a series of process steps to ultimately lead to the synthesis of various 7-oxo-1,6-diazabicyclo[3.2.1]octanes suitable for use as β-lactamase inhibitors, including (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfato)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. One such process step, identified as Step F in US 9,604,985, is sulfation, wherein a hydroxide compound of the following structure is reacted:

[0010] Contacting with a sulfating agent in the presence of an organic base to form a sulfonated compound: The sulfating agent in step F is suitably a complex of sulfur trioxide and an amine, wherein the amine is suitably a tertiary amine, including, for example, acyclic amines (e.g., trimethylamine), TEA, DIPEA, dimethylphenylamine and dimethylbenzylamine), cyclic amines (e.g., 1-methylpyrrolidine and 1-methylpiperidine) and aromatic amines having one or more N atoms as part of an aromatic ring (e.g., 1-methylimidazole, pyridine and pyrimidine). A halosulfonic acid (e.g., chlorosulfonic acid) and SO 3 Tertiary amide complexes (e.g. DMF-SO 3 ) are also suitable sulfating agents. One class of suitable sulfating agents consists of complexes of the following amines with sulfur trioxide: pyridine, trimethylamine, and triethylamine. Another class of suitable sulfating agents consists of pyridine-SO 3 Complex, DMF-SO 3 The sulfating agent is generally used in an amount ranging from about 1.5 to about 7.0 equivalents per equivalent of the above-mentioned hydroxyurea compound VIII.

[0011] The required organic base is suitably pyridine or a tertiary amine, such as 2-picoline, 2,6-lutidine, a separate coltidine, or a mixture of two or more coltidines. One class of suitable bases consists of picolines (e.g., 2-picoline), 2,6-lutidine, and 2,4,6-collidine. US 9,604,985 discloses that the preferred base is 2-picoline or pyridine. The base is typically used in an amount ranging from about 1 to about 3 equivalents per equivalent of the hydroxyurea compound mentioned above.

[0012] SP Miller et al. discussed in detail the optimization of the synthesis of (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfate)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide taught in US 9,604,985 (see SP Miller et al., "Practical and Cost-Effective Manufaturing Route for the Synthesis of a β-Lactamase Inhibitor", Org. Lett. 2014, 16, 174-177). Finally, both the routes described in SPMiller et al. and US9,604,985 contain cumbersome four-step processes that require the use of two protecting groups to form tert-butyl 4-((2S,5S)-1-((2-nitrophenyl)sulfonyl)-5-(((nitrophenyl)sulfonyl)oxy)piperidine-2-carboxamido)piperidine-1-carboxylate as an intermediate. In addition, both references describe subsequent process steps and intermediates required to ultimately produce the relevant β-lactamase inhibitors. One of these steps involves the sulfation of the hydroxyurea intermediate, which requires the hydroxyurea intermediate to be exposed to a sulfating agent and an organic base (see Step F in US 9,604,985).

[0013] It would be beneficial to discover alternative methods that reduce or eliminate, where possible, the need for cumbersome steps or excess reagents without causing deleterious effects on process yields, thereby resulting in more efficient and economically viable processing methods. SUMMARY OF THE INVENTION

[0015] The present invention relates to a method for preparing an intermediate which can be used for synthesizing a beta-lactamase inhibitor (2S, 5R)-7-oxo-N-piperidin-4-yl-6-(sulfate)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.

[0016] One embodiment of the present invention is an efficient two-step method for preparing a compound of formula I or a salt thereof

[0017]

[0018] It includes:

[0019] A) in a first organic solvent, N -(3-Dimethylaminopropyl)- N '-ethylcarbodiimide hydrochloride (EDC), 1-hydroxy-2-pyridone (HOPO) and at least one acid to couple pipecolic acid with an azacycloalkylamine to form a compound of formula II

[0020] and

[0021] B) contacting a compound of formula (II) with a protecting group in the presence of a nucleophilic catalyst and a second organic solvent to form a compound of formula (I).

[0022] The compounds of formula I are useful as intermediates in the production of beta-lactamase inhibitors.

[0023] This improved two-step process eliminates the need for lactone formation and the need to use two different protecting group steps as taught in US 9,604,095 and SP Miller et al.

[0024] Another aspect of the present invention relates to the unexpected and surprising discovery that elimination of the chemical reagents in the sulfation described and exemplified as step F in US 9,604,985 can lead to the preparation of a compound of formula (IV) or a pharmaceutically acceptable salt thereof

[0025] ,

[0026] The process of the present invention also improves process robustness because sulfation under the new conditions produces a homogeneous solution rather than a thick slurry.

[0027] Other embodiments, aspects and features of the present invention are further described in or are obvious from the ensuing description, examples and appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] These and other features of the present invention will become more apparent from the following detailed description and accompanying drawings, in which:

[0030] Figure 1 Display when using different SO 3 Amine complexes, specifically, using SO 3 -TEA complex vs SO 3 -Py (SO 3 -pyridine) complexes, the difference in the reaction mixture during the sulfation step. DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention relates to a process for preparing compounds of formula I by coupling pipecolic acid with an azacycloalkylamine to form an intermediate used in a process for preparing the beta-lactamase inhibitor (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfate)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.

[0033] As mentioned previously, the improved process of the present invention provides a two-step synthesis of compounds of Formula I, rather than the four-step process disclosed in US 9,604,095 and SP Miller et al. The process of the present invention eliminates the need for lactone formation and the need to use two different protecting group steps as required by US 9,604,095 and SP Miller et al. In the process of the present invention, the protecting group (e.g., nitrobenzenesulfonyl chloride) is used only once and installed in one step, rather than twice as it is used in the process described by Miller et al. and US 9,604,095, because the lactone formation step is no longer required.

[0034] One embodiment of the present invention is a process for preparing a compound of formula I,

[0035]

[0036] It includes:

[0037] A) in a first organic solvent, N -(3-Dimethylaminopropyl)- N '-ethylcarbodiimide hydrochloride (EDC), 1-hydroxy-2-pyridone (HOPO) and at least one acid to couple pipecolic acid with an azacycloalkylamine to form a compound of formula II

[0038] and

[0039] B) contacting a compound of formula (II) with a protecting group in the presence of a nucleophilic catalyst and a second organic solvent to form a compound of formula I.

[0040] In one embodiment of the present invention, in step A), pipecolic acid is And the azacycloalkylamine is

[0041] And the at least one acid is selected from aqueous hydrochloric acid or methanesulfonic acid (MsOH).

[0042] In another embodiment of the present invention, the first organic solvent can be any suitable organic solvent, i.e., a solvent in which the reactants are soluble or partially soluble. Suitable organic solvents include, but are not limited to, DCM, DMF, AcNMe 2 (N,N-dimethylacetamide), THF, MeTHF (2-methyltetrahydrofuran), EtOAc, i-PrOAc (isopropyl acetate), acetonitrile and mixtures thereof. The preferred solvent is acetonitrile.

[0043] In another embodiment of the present invention, the second organic solvent can be any suitable organic solvent, i.e., a solvent in which the reactants are soluble or partially soluble. Suitable organic solvents include, but are not limited to, DCM, DMF, AcNMe 2 (N,N-dimethylacetamide), THF, MeTHF (2-methyltetrahydrofuran), EtOAc, i-PrOAc (isopropyl acetate), acetonitrile and mixtures thereof. The preferred solvent is acetonitrile.

[0044] In another embodiment of the present invention, in step B), the nucleophilic catalyst is 4-dimethylaminopyridine (DMAP) and the organic solvent is acetonitrile (MeCN).

[0045] In one embodiment of the present invention, the protecting group is a sulfonyl group generated from a sulfonyl halide, such as methanesulfonyl chloride, chloromethanesulfonyl chloride, dichloromethanesulfonyl chloride, benzenesulfonyl chloride, p-trifluoromethylbenzenesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-fluorobenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2,4-dichlorobenzenesulfonyl chloride and p-trifluoromethylbenzenesulfonyl chloride.

[0046] In another embodiment of the present invention, the protecting group is selected from the group consisting of chloromethanesulfonyl chloride, p-trifluoromethylbenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride and 2,4-dichlorobenzenesulfonyl chloride.

[0047] In one embodiment of the invention, the protecting group is selected from 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride and mixtures thereof. In a variation of this embodiment, the nitrobenzenesulfonyl chloride is 2-nitrobenzenesulfonyl chloride (2-NsCl). In yet another embodiment, the nitrobenzenesulfonyl group is 4-nitrobenzenesulfonyl group (4-NsCl).

[0048] In one embodiment of the method of the present invention, in step A) of the method for synthesizing the compound of formula (I) or a salt thereof, the coupling comprises the following steps:

[0049] 1) adding an azacycloalkylamine of formula (A2) to acetonitrile to form a mixture,

[0050] 2) adding at least one acid selected from aqueous hydrochloric acid or MsOH to the mixture of step 1;

[0051] 3) adding HOPO and pipecolic acid of formula (A1) to the mixture of step 2, and then heating the mixture to a temperature of about 20° C. to about 50° C.; and

[0052] 4) Add EDC to the heated mixture from step 3.

[0053] In another aspect of the invention, the at least one acid is aqueous hydrochloric acid. In another aspect of the invention, the at least one acid is methanesulfonic acid (MsOH).

[0054] In one embodiment of the invention, the temperature is between about 20°C and about 50°C. In one aspect of this embodiment, the temperature is about 40°C.

[0055] In one aspect, the aqueous hydrochloric acid concentration is about 6N to concentrated HCl (37 wt%). In one embodiment of the present invention, concentrated HCl (37 wt%) is used.

[0056] Another aspect of the present invention relates to an unexpected and surprising improvement to the general sulfation step, Step F, described in US Pat. No. 9,604,985 to Miller et al. (the "'985 Patent"). As mentioned above, Step F of the '985 Patent requires sulfating a hydroxyurea compound with a sulfating agent in the presence of an organic base such as pyridine, 2-picoline, 2,6-lutidine, or collidine. The present inventors have discovered that the elimination of the organic base and the appropriate SO 3 The use of amine complexes produces SO in the presence of organic bases and pyridine 3 A complex is a more homogeneous mixture produced when a heterogeneous mixture is made.

[0057] One aspect of the present invention relates to a method for preparing a compound of formula IV:

[0058]

[0059] It includes:

[0060] contacting a hydroxyurea of ​​formula (III) in the presence of sulfur trioxide amine selected from sulfur trioxide-triethylamine, sulfur trioxide-tripropylamine, and sulfur trioxide-tributylamine and at least one solvent selected from 2-methyltetrahydrofuran and tetrahydrofuran to form a reaction mixture;

[0061]

[0062] adding an aqueous solution of dipotassium hydrogen phosphate to the reaction mixture; and

[0063] Tetrabutylammonium hydrogen sulfate is added to form compound (IV) in a two-phase mixture.

[0064] The SO used in the sulfation process of the present invention 3 - Careful selection of the amine complex and solvent results in a yield of greater than about 90% converted compound of formula (VI). One embodiment of the present invention results in greater than 97% within 5 hours. In addition, SO of the present disclosure 3 - The use of the amine complex and solvent system in the sulfation of the present invention results in robust process conditions with a homogeneous reaction mixture.

[0065] Figure 1 Diagram of using different SO 3 Amine complexes, specifically, SO 3 -TEA complex and SO 3 -Py (SO 3 -pyridine) complex, the type of reaction mixture produced during the above-mentioned sulfation process. Figure 1 As can be seen, using SO 3 The sulfation of the -TEA complex produced a homogeneous solution, whereas the use of SO3 Sulfation of the -Py complex and picoline produces a thick slurry. From a mass transport processing perspective, it is more desirable to provide a homogeneous solution because it is easier to scale up.

[0066] Another embodiment of the present invention is the formation of a compound of formula (V)

[0067]

[0068] It includes:

[0069] contacting compound (IV) with trimethylsilyl bromide (TMSBr) in the presence of an organic solvent; and

[0070] Tetrabutylammonium acetate-acetic acid complex in acetonitrile and water is added to form compound (V).

[0071] The method of preparing Compound (V) further comprises adding isopropyl alcohol to the mixture containing Compound (V) and filtering the resulting solution.

[0072] In one embodiment of the invention, isopropanol is added in a range of about 4x to about 7x volume relative to Compound IV.

[0073] In one embodiment of the present invention, the tetrabutylammonium acetate-acetic acid complex is present in an amount ranging from about 0.1 to about 0.45 equivalents per equivalent of the sulfate compound of formula (IV).

[0074] In another embodiment of the present invention, the organic solvent can be any suitable organic solvent, i.e., a solvent in which the reactants are soluble. Suitable organic solvents include, but are not limited to, DCM, DMF, AcNMe 2 (N,N-dimethylacetamide), THF, MeTHF (2-methyltetrahydrofuran), EtOAc, i-PrOAc (isopropyl acetate), acetonitrile and mixtures thereof. The preferred solvent is acetonitrile.

[0075] Another embodiment of the present invention includes the synthesis of the beta-lactamase inhibitor (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfate)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide using the intermediates and process improvements of the present invention. Scheme A provides an overview of the general method for preparing (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfate)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.

[0076] Plan A

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083] Compounds such as (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfato)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide can exhibit inhibition of β-lactamases and therefore can be used as β-lactamase inhibitors in combination with β-lactam antibiotics (e.g., imipenem, ceftazidime, and piperacillin) to treat bacterial infections caused by microorganisms that are usually resistant to β-lactam antibiotics due to the presence of β-lactamases.

[0084] It is to be understood that the solvents, reagents, catalysts, reaction amounts, reaction temperatures, etc. described above with respect to the method and its embodiments and sub-embodiments are intended only to illustrate and not to limit the scope of the method. For example, the solvent used in any step (a) to (c) can be any organic substance that is in the liquid phase, chemically inert, and will dissolve, suspend, and / or disperse the reactants and any reagents under the reaction conditions used in the relevant step to contact the reactants and reagents and allow the reaction to proceed. Similar considerations apply to the selection of alkalis, catalysts, and other reagents used in the process steps. In addition, each step can be carried out at any temperature at which the reaction to form the desired product is appreciably carried out. The reactants, catalysts, and reagents in a given step can be used in any amount that results in the formation of at least some desired products. Of course, high conversion (e.g., at least about 60% and preferably higher) of the raw materials combined with a high yield (e.g., at least about 60% and preferably higher) of the desired product is generally the goal of each step, and the selection of solvents, reagents, catalysts, reaction amounts, temperatures, etc. that can provide relatively good conversion and product yields is preferred, and the selection that can provide the best conversion and yield is more preferred. The specific solvents, reagents, catalysts, reaction amounts, reaction temperatures, etc. described above with respect to the process and embodiments and subembodiments thereof may provide good to optimal conversions and yields.

[0085] The reaction time of the above process steps depends on the following factors: (i) the choice and relative proportions of the starting substrate and other reagents, (ii) the choice of solvent, (iii) the choice of reaction temperature and (iv) the desired conversion level. The reaction is usually carried out for a time sufficient to achieve 100% or nearly 100% conversion (e.g., 99.5%, 99.0%, 98.0%, 97.0% or 95%).

[0086] The progress of any reaction step described herein can be followed by monitoring the disappearance of reactants and / or the appearance of desired products using analytical techniques such as TLC, HPLC, IR, NMR or GC.

[0087] Abbreviations used herein include the following:

[0088] BLI β-lactamase inhibitors Bn Benzyl Boc tert-Butyloxycarbonyl Cb Benzyloxycarbonyl (or, benzyloxycarbonyl) CDI Carbonyldiimidazole DCM Dichloromethane DIPEA Diisopropylethylamine (or Hunig's base) DMAC or DMAc N,N-Dimethylacetamide DABCO 1,4-Diazabicyclo[2.2.2]octane DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide E Ethyl EtOAc Ethyl acetate GC Gas chromatography HPLC High performance liquid chromatography IPA Isopropyl alcohol IPA Isopropyl acetate IR Infrared LCAP Liquid chromatogram area percentage Me methyl MeCN Acetonitrile MeOH Methanol MTBE Methyl tert-butyl ether 4-NMM 4-Methylmorpholine NMP N-Methylpyrrolidone NMR Nuclear Magnetic Resonance PG Protecting Group RB Round bottom t-Bu Tert-butyl TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography

[0089] The following examples are intended to illustrate the present invention and its practice only. The examples should not be construed as limiting the scope or spirit of the present invention.

[0090] Example 1

[0091] (2S,5R)-7-Oxo-N-piperidin-4-yl-6-(sulfate)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

[0092] Step 1 Amidation

[0093] 4-((2 S ,5 S )-5-Hydroxypiperidine-2-carboxamido)piperidine-1-carboxylic acid tert-butyl ester (1-c)

[0094]

[0095] To a mixture of 4-amino-1-Boc-piperidine (1-b) (20 g, 98 wt%, 0.1 mol) in acetonitrile (400 mL) was added 37 wt% HCl (9.85 g, 0.1 mol) dropwise over 1 hour. Then HOPO (8.3 g, 0.075 mol) and (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (1-a) (16.7 g, 98 wt%, 0.115 mol) were added. The batch was heated to 40°C and EDC HCl (26.8 g, 0.14 mol) was added. The reaction mixture was aged at 40 ‒ 45°C for at least 5 h and then cooled to 20 ‒ 25°C. NaOH (5M, 140 mL) and methyl tert-butyl ether (120 mL) were added. The separated organic layer was washed with 5M NaOH (40 mL x 3).

[0096] The organic layer solvent was switched to acetonitrile, final volume ~120 mL. Methyl tert-butyl ether (180 mL) was added over 1 hour. The batch was filtered and the filter cake was washed with MTBE (100 mL x 2). Vacuum oven drying at 40 ‒ 45 °C gave the desired product (1-c).

[0097]

[0098] Step 2 Bisnitrobenzene sulfonylation

[0099] 4-((2 S ,5 S )-1-((4-nitrophenyl)sulfonyl)-5-(((4-nitrophenyl)sulfonyl)oxy)piperidin-2-yl (formamido)piperidine-1-carboxylic acid tert-butyl ester hydrate (1-e)

[0100]

[0101] To a mixture of amide intermediate (1-c) (33.4 g, 98 wt%, 0.1 mol) and DMAP (29.3 g, 0.24 mol) in acetonitrile (300 mL) was added dropwise a solution of 4-nitrobenzenesulfonyl chloride (1-d) (48.8 g, 0.22 mol) in acetonitrile (130 mL) at ambient temperature. The reaction was aged for several hours until the reaction was complete. Water (130 mL) was then added at ambient temperature and the batch was seeded with dinitrobenzenesulfonylamide. Additional water (330 mL) was added over 6 hours. After filtration, the wet cake was washed with 50% aqueous MeCN (270 mL). Vacuum oven drying at 40 °C provided the desired product (1-e).

[0102]

[0103] Step 3: Diamine pTSA Salt

[0104]

[0105] Benzyloxysulfonamide (10.2 g, 33.0 mmol), K 2 CO 3 A mixture of (4.4 g, 31.6 mmol) in DMAc (40 mL) was stirred at 50 °C for several hours. N,O -bis(nitrobenzenesulfonyl)amide 1-e (20.0 g, 28.7 mmol), the reaction mixture was stirred at 55 °C until the reaction was deemed complete. MeOH (200 mL) and thioglycolic acid (11.9 g, 129.2 mmol) were added at ambient temperature. K 2 CO 3(35.7 g, 258.3 mmol). The reaction mixture was stirred at 0 °C until the reaction was deemed complete. Water (200 mL) and toluene (120 mL) were added to the reaction mixture. The organic phase was separated and the aqueous layer was extracted with toluene (60 mL). The combined organic phases were treated with 5 wt% K 2 CO 3 (40 mL x 2), followed by 5 wt % NaCl (40 mL) wash. The organics were concentrated in vacuo at 35 °C to ~100 mL.

[0106] To a solution of the diamine free base (10.0 g assay, 23.1 mmol) at 40 °C was added p-toluenesulfonic acid (4.0 g, 23.1 mmol) in MeCN (25 mL) dropwise. p After TSA / MeCN solution, the batch was seeded with diamine pTSA salt crystals. After the addition of pTSA, the slurry was stirred at 0 °C for several hours and then filtered. The wet cake was washed with acetonitrile / toluene solution (1:3 v / v, 20 mL x 3). Vacuum oven drying at <70 °C provided the desired diamine pTSA salt.

[0107]

[0108] Step 4 Benzyl urea intermediate

[0109]

[0110] Diamine p TSA salt 1-h (10.0 g, 16.54 mmol) and N , N -Diisopropylethylamine (i-Pr 2 A mixture of NEt) (4.9 mL, 28.12 mmol equiv.) in acetonitrile (MeCN) (50 mL) was azeotropically dried in vacuo at 50 °C in a volume of ~30 mL. The batch was then diluted to ~60 mL with MeCN and additional i-Pr 2 NEt (10.1 mL, 57.89 mmol). The reaction mixture was cooled to 10°C. Dimethyldichlorosilane (Me 2 SiCl 2) (2.8 mL, 23.16 mmol) while maintaining the internal temperature at 10 °C. The reaction mixture was stirred at 10 °C for an additional 1-2 hours. Carbonyldiimidazole (CDI) (4.0 g, 24.81 mmol) was then added at ambient temperature and the batch was stirred at 45 °C until the reaction was deemed complete. IPA (5.1 mL, 66.16 mmol) was then added dropwise at 45 °C. The batch was stirred at 45 °C until the reaction was deemed complete. Toluene (50 mL) was then added dropwise followed by 2M HCl (40 mL) while maintaining the temperature at 5 °C. The separated organic phase was treated with 2M HCl (40 mL) followed by 5 wt% sodium bicarbonate (NaHCO 3 ) (20 mL). Activated carbon (3.0 g) was loaded into the organic layer. The mixture was stirred at 55 °C and then cooled to ambient temperature. The filtrate was concentrated to approximately 30 mL at 45 °C and the batch was seeded with benzyl urea crystals. Heptane (82 mL) was added at 45 °C over several hours. The slurry was then cooled to 10 °C and then filtered. The wet cake was washed with 20% toluene / heptane solution (20 mL). Vacuum oven drying at less than about 60 °C produced the desired product 1-i. NMR data matched those previously reported [ WO 2016 / 089718 A1 ].

[0111] Step 5 Hydrogenolysis

[0112] 4-((1 R ,2 S ,5 R )-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin Tert-Butylpyridine-1-carboxylate (1-j)

[0113]

[0114] Palladium on carbon (Pd / C) (5%, 50% water wet, 4.6 g) was azeotropically dried with isopropyl acetate (IPAc) to a final volume of approximately 550 mL. Benzyl urea (458.6 g, 0.1 mol), N,O-Bis(trimethylsilyl)acetamide (95%, 32.2 mL, 0.125 mol) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (0.224 g, 0.002 mol) were added to the catalyst and IPAc mixture. The batch was hydrogenated at 50 psig and 20°C until the reaction was complete. The catalyst was filtered and washed with IPAc (275 mL). The combined filtrates were concentrated under reduced pressure to a final volume of approximately 640 mL. A portion of a solution of acetic acid (5.4 g, 0.07 mol) and water (4.7 g, 0.26 mol) was combined with a portion of the batch solution and seeded with hydroxyurea. The remaining batch solution and aqueous acetic acid were mixed and aged for several hours. Methyl tert-butyl ether (MTBE) (275 mL) was added and the mixture was then cooled to 15-20°C. The batch was then filtered and the wet cake was washed with 20% MTBE / IPAc solution (140 mL). Drying in a vacuum oven at 40 °C yielded 1-j. The NMR data matched those previously reported as WO Those reported in the international application published in 2018 / 053057.

[0115] Step 6: Sulfation

[0116] (1 R ,2 S ,5 R )-2-((1-(tert-Butyloxycarbonyl)piperidin-4-yl)carbamoyl)-7-oxo-1,6-diazo Heterobicyclo[3.2.1]octan-6-yltetrabutylammonium sulfate (1-k)

[0117]

[0118] Hydroxyurea 1-j (10.0 g, 27.1 mmol) and SO 3 • A mixture of TEA (7.4 g, 40.7 mmol) in 2-methyltetrahydrofuran (2-MeTHF) (100 mL) was stirred at 38 °C until the reaction was complete. The batch was then cooled to ambient temperature. Potassium dihydrogen phosphate (K 2 HPO 4 ) (8.5 g, 48.9 mol) in water (130 mL). Then tetrabutylammonium hydrogen sulfate (Bu 4 NHSO 4 ) (10.1 g, 29.9 mmol) and the biphasic mixture was stirred for ≥0.5 h. The organic phase was separated and the aqueous phase was extracted with 2-MeTHF (60 mL). The combined organic phases were washed with aqueous sodium chloride (20 wt %, 50 mL). The organic phase azeotropic solvent was switched to acetonitrile with a volume of ≥50 mL. The batch was treated with activated carbon (≥1 g). The batch was filtered and the filtrate containing compound 1-k was azeotropically concentrated and used directly "as is" in the subsequent step 5.

[0119] Step 5 Boc deprotection

[0120]

[0121] To a solution of Boc sulfate 1-k (11.17 mmol, 5.0 g of sulfate anion assayed) in MeCN (50 mL) was added trimethylsilyl bromide (TMSBr) (15.08 mmol, 2.31 g) at ambient temperature. The reaction mixture was stirred overnight. A solution of tetrabutylammonium acetate-acetic acid complex (2.79 mmol, 1.09 g) in MeCN (5.0 mL) and water (6.0 mL) was added over 1 hour. After stirring the mixture for several hours, IPA (30 mL) was subsequently added over 3 hours. The batch was stirred for 2-24 hours and then filtered. The wet cake was washed with IPA / water (90:10) solution (15 mL x2). Suction drying yielded the desired product 1-l. NMR data matched those reported previously. (See, e.g., Miller SP et al., “Practical and Cost-Effective Manufacturing Route for the Synthesis of a β-Lactamase Inhibitor”. Organic Letters 2014 16 (1), 174-177).

[0122] While the above description teaches the principles of the invention by means of embodiments provided for illustration, the practice of the invention encompasses all common changes, adaptations and / or modifications that fall within the scope of the following claims.

Claims

1. Method for preparing a compound of formula (I) or a salt thereof It includes: A) coupling pipecolic acid with an azacycloalkylamine in the presence of a first organic solvent, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxy-2-pyridone (HOPO) and at least one acid to form a compound of formula (II) and B) contacting the compound of formula (II) with a protecting agent in the presence of a nucleophilic catalyst and a second organic solvent to form a compound of formula (I), wherein the protecting agent is 4-nitrobenzenesulfonyl chloride, Wherein in step A) pipecolic acid is And the azacycloalkylamine is and The compound of formula (I) is 2. The process of claim 1, wherein in step A), the at least one acid is selected from aqueous hydrochloric acid or methanesulfonic acid (MsOH).

3. The method of claim 1, wherein the first organic solvent is selected from the group consisting of DCM, DMF, AcNMe2, THF, MeTHF, EtOAc, i-PrOAc and acetonitrile and mixtures thereof.

4. The method of claim 1, wherein the second organic solvent is selected from the group consisting of DCM, DMF, AcNMe2, THF, MeTHF, EtOAc, i-PrOAc and acetonitrile and mixtures thereof.

5. The method of claim 3 or 4, wherein the first and second organic solvents are acetonitrile.

6. The method of claim 1, wherein the nucleophilic catalyst is 4-dimethylaminopyridine (DMAP).

7. A method for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof: It includes: contacting a hydroxyurea of ​​formula (III) in the presence of sulfur trioxide amine selected from sulfur trioxide-triethylamine, sulfur trioxide-tripropylamine, and sulfur trioxide-tributylamine and at least one solvent selected from 2-methyltetrahydrofuran and tetrahydrofuran to form a reaction mixture; adding an aqueous solution of dipotassium hydrogen phosphate to the reaction mixture; and Tetrabutylammonium hydrogen sulfate is added to form compound (IV) in a two-phase mixture.

8. The method of claim 7, further comprising forming a compound of formula (V) It includes: contacting compound (IV) with trimethylsilyl bromide (TMSBr) in the presence of an organic solvent; and Tetrabutylammonium acetate-acetic acid complex in acetonitrile and water is added to form compound (V).

9. The method of claim 8, further comprising adding isopropanol to the reaction mixture containing compound (V) and filtering the resulting mixture.

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