Crystal form of Durulobacterium

Abstract

In this specification, formula I: The salt forms of DUR (DUR) having TIFF2025516043000051.tif3965 are provided. In particular, the crystalline forms of DUR-TBA, DUR-TEA, and DUR-Ca are provided. Methods for preparing these salts and the characterization of their various polymorphic forms are also provided. Furthermore, the present invention includes methods for synthesizing DUR-Na from the various crystalline DUR salts disclosed.

Description

Related Applications

[0001] Related Applications

[0001] This application claims priority to International Application No. PCT / CN2022 / 090815, filed on April 29, 2022, the entire content of which is incorporated herein by reference.

Background Art

[0002]

[0002] Durlobactam (DUR, formerly known as ETX2514) is a novel and broad-spectrum potent inhibitor of class A, C, and D β-lactamases. Sulbactam (SUL) is a β-lactam antibiotic active against Acinetobacter baumannii, but β-lactamase-mediated sulbactam resistance has now spread widely, and sulbactam is generally ineffective. In preclinical studies, durlobactam has been found to inhibit β-lactamases commonly found in A. baumannii and restore the activity of sulbactam. Currently, a SUL-DUR combination product (also referred to as sulbactam-durlobactam) is being developed for the treatment of severe infections caused by Acinetobacter, including multidrug-resistant (MDR) strains.

[0003]

[0003] The sodium salt of DUR is the active pharmaceutical ingredient used for intravenous injection and is described in Example 10 of WO2013 / 150296. The process for preparing the sodium salt of DUR includes first forming a phosphonium salt and then exchanging it with sodium via an ion exchange resin. However, the phosphonium salt cannot be crystallized and its purity is less than 95%. In addition, the phosphonium salt is not amendable to large-scale batches (e.g., several kilograms) required for large-scale production.

Summary of the Invention

Problems to be Solved by the Invention

[0004] Therefore, there is a need for chemical precursors and methods that enable the large-scale production of DUR, particularly its sodium salt. Means for Solving the Problems

[0005] Summary

[0005] The present specification provides a crystalline form of durulobacterium that can be used for the large-scale preparation of the sodium salt of durulobacterium. Such a crystalline form has the formula I

[0006]

Chemical formula

[0007] (wherein X and n are as defined herein) including those having.

[0006] In one aspect, the crystalline forms described herein include durulobacterium tetrabutylammonium salt (DUR-TBA), durulobacterium triethylammonium salt (DUR-TEA), durulobacterium calcium salt (DUR-Ca), all of which are different from the phosphonium salts previously described in Example 10 of WO2013 / 150296 and have been found to be suitable for the preparation of multiple kilograms of durulobacterium sodium salt (DUR-Na).

[0008]

[0007] Also provided herein are polymorphic forms of the disclosed DUR-TBA, DUR-TEA, DUR-Ca.

[0008] Methods for making the disclosed DUR-TBA, DUR-TEA, DUR-Ca, and their polymorphic forms are further provided.

[0009]

[0009] Methods for making DUR-Na from the disclosed DUR-TBA, DUR-TEA, DUR-Ca, and their polymorphic forms are further provided. Brief Description of the Drawings

[0010]

Figure 1

Figure 2

[0011] Graph showing the TGA and DSC of DUR-TBA Form A.

Figure 3

[0012] FIG. showing the XRPD of DUR-TEA Form A.

Figure 4

[0013] Graph showing the TGA and DSC of DUR-TEA Form A.

Figure 5

[0014] FIG. showing the XRPD of DUR-Ca Form B.

Figure 6

[0015] Graph showing the TGA and DSC of DUR-Ca Form B.

Figure 7

[0016] FIG. showing the XRPD of DUR-Ca Form A.

Figure 8

[0017] Graph showing the TGA of DUR-Ca Form A.

Figure 9

[0018] Graph showing the DSC of DUR-Ca Form A.

Figure 10

[0019] FIG. showing the XRPD of DUR-Ca Form C.

Figure 11

[0020] Graph showing the TGA of DUR-Ca Form C.

Figure 12

[0021] Graph showing the DSC of DUR-Ca Form C.

Figure 13

[0022] FIG. showing the XRPD of DUR-Ca Form F.

Figure 14

[0023] Graph showing the TGA and DSC of DUR-Ca Form F.

Figure 15

[0024] FIG. showing the overview of DUR-Ca crystal forms.

MODE FOR CARRYING OUT THE INVENTION

[0011]

[0025] Formula I

[0012]

Chem.

[0013] (wherein, n is 1 or 2, X is a positively charged amine or a Ca, Mg, Zn, K, Na, Li, Cs, Ba, Rb, Sr, Fe, Co, Ni, Cu, Zn, Ag, or Au cation) The salt form of DUR having the same is provided.

[0014]

[0026] As used herein, "crystal" refers to a solid form of DUR in which atoms form a three-dimensional array within a single repeating unit called a unit cell. The crystallinity of DUR can be confirmed, for example, by examination of an X-ray powder diffraction pattern.

[0015]

[0027] "Single crystal form" means that DUR exists as a single crystal or as a plurality of crystals each having the same crystal form. The weight percentage of a particular crystal form is determined by dividing the weight of the particular crystal form by the total weight of the particular crystal, plus the weight of the other crystal forms present, plus the weight of the amorphous form present, and multiplying by 100%. "Pure single crystal form" means that DUR exists as a single crystal or as a plurality of crystals each having the same crystal form and in which no other detectable amount of crystal form is present.

[0016]

[0028] Chemical purity refers to the extent to which the disclosed form contains no substances having different chemical structures. The chemical purity of DUR in the disclosed crystal form means the weight of DUR divided by the total weight of DUR plus the weight of substances / impurities having different chemical structures, multiplied by 100%, i.e., the weight percentage.

[0017]

[0029] The term "amorphous" refers to a DUR that exists in an amorphous state or form. Since an amorphous solid is a disordered arrangement of molecules, it has no identifiable crystal lattice or unit cell and thus no definable long-range order. The solid-state order of a solid can be determined by standard techniques known in the art, such as X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).

[0018]

[0030] The 2-theta (2Θ) values of the X-ray powder diffraction patterns of the crystalline forms described herein may vary slightly from instrument to instrument and may also vary slightly due to sample preparation variations and batch-to-batch variations caused by factors such as temperature variations, sample displacement, and the presence or absence of an internal standard. Therefore, unless otherwise defined, the XRPD patterns / enumerations listed herein should not be interpreted as absolute and may vary by ±0.2 degrees. This variability is well known in the art to account for the above factors without preventing the clear identification of the crystalline form. Unless otherwise specified, the 2-theta values provided herein were obtained using Cu Kα1 radiation.

[0019]

[0031] Temperature values such as DSC peaks in this specification may vary slightly from instrument to instrument and may also vary slightly due to sample preparation variations, batch-to-batch variations, and environmental factors. Therefore, unless otherwise defined, the temperature values listed herein should not be interpreted as absolute values and may vary by ±5 degrees or ±2 degrees.

[0020]

[0032] "Substantially the same XRPD pattern" or a defined figure and "substantially similar X-ray powder diffraction pattern" mean that at least 90% of the peaks shown are present for comparison purposes. It should be further understood that for comparison purposes, some variation in peak intensity from the peak intensity shown, for example ±0.2 degrees, is tolerated.

[0021]

[0033] In the first embodiment, X of the salt of formula I is a positively charged amine or a Ca cation. Alternatively, as part of the first embodiment, X of the salt of formula I is a positively charged amine. In another alternative, as part of the first embodiment, X of the salt of formula I is a tertiary amine or a quaternary amine. In another alternative, as part of the first embodiment, X of the salt of formula I is trimethylammonium, triethylammonium, tributylammonium, triisopropylammonium, or N,N - diisopropylethylammonium. In another alternative, as part of the first embodiment, X in the salt of formula I is triethylammonium.

[0022]

[0034] In the second embodiment, the salt of formula I has the structural formula:

[0023]

Chemical formula

[0024] and is referred to herein as durulobacterium triethylammonium salt (DUR - TEA).

[0035] In the third embodiment, the salt of formula I or (DUR - TEA) is crystalline.

[0025]

[0036] In the fourth embodiment, DUR-TEA is in crystalline form A. Alternatively, as part of the fourth embodiment, DUR-TEA is in crystalline form A and is characterized by at least three X-ray powder diffraction peaks at 2Θ angles selected from 9.5°, 10.7°, 12.7°, 13.5°, 17.3°, 22.6°, and 24.4°. In another alternative, as part of the fourth embodiment, DUR-TEA is in crystalline form A and is characterized by at least four X-ray powder diffraction peaks at 2Θ angles selected from 9.5°, 10.7°, 12.7°, 13.5°, 17.3°, 22.6°, and 24.4°. In another alternative, as part of the fourth embodiment, DUR-TEA is in crystalline form A and is characterized by at least five X-ray powder diffraction peaks at 2Θ angles selected from 9.5°, 10.7°, 12.7°, 13.5°, 17.3°, 22.6°, and 24.4°. In another alternative, as part of the fourth embodiment, DUR-TEA is in crystalline form A and is characterized by at least six X-ray powder diffraction peaks at 2Θ angles selected from 9.5°, 10.7°, 12.7°, 13.5°, 17.3°, 22.6°, and 24.4°. In another alternative, as part of the fourth embodiment, DUR-TEA is in crystalline form A and is characterized by X-ray powder diffraction peaks at 2Θ angles of 9.5°, 10.7°, 12.7°, 13.5°, 17.3°, 22.6°, and 24.4°. In another alternative, as part of the fourth embodiment, DUR-TEA is in crystalline form A and is characterized by at least three, at least four, at least five, at least six, or at least seven X-ray powder diffraction peaks at the 2Θ angles listed in Table 16.

[0026]

[0037] In the fifth embodiment, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 95 wt%, or at least 99 wt% of the DUR-TEA crystalline form A is in the single crystal form, and optionally, in the fourth embodiment, it is characterized by the XRPD peaks listed above. Alternatively, as part of the fifth embodiment, the DUR-TEA crystalline form A is optionally present in a pure crystalline form characterized by the XRPD peaks listed above in the fourth embodiment.

[0027]

[0038] In the sixth embodiment, the DUR-TEA crystalline form A is characterized by an X-ray powder diffraction pattern substantially similar to that of FIG. 3.

[0039] In the seventh embodiment, X in the salt of formula I is tetrabutylammonium, tetraethylammonium, tetramethylammonium, or tetrapropylammonium. Alternatively, as part of the seventh embodiment, X in the salt of formula I is tetrabutylammonium.

[0028]

[0040] In the eighth embodiment, the salt of formula I has the structural formula:

[0029]

Chemical formula

[0030] and is referred to herein as durulobactam tetrabutylammonium salt (DUR-TBA).

[0041] In the ninth embodiment, the salt of formula I or DUR-TBA is crystalline.

[0031]

[0042] In the 10th embodiment, DUR-TBA is in crystalline form A. Alternatively, as part of the 10th embodiment, DUR-TBA is in crystalline form A and is characterized by at least three X-ray powder diffraction peaks at 2Θ angles selected from 7.3°, 8.5°, 8.7°, 10.3°, 12.7°, 19.5°, and 21.4°. In another alternative, as part of the 10th embodiment, DUR-TBA is in crystalline form A and is characterized by at least four X-ray powder diffraction peaks at 2Θ angles selected from 7.3°, 8.5°, 8.7°, 10.3°, 12.7°, 19.5°, and 21.4°. In another alternative, as part of the 10th embodiment, DUR-TBA is in crystalline form A and is characterized by at least five X-ray powder diffraction peaks at 2Θ angles selected from 7.3°, 8.5°, 8.7°, 10.3°, 12.7°, 19.5°, and 21.4°. In another alternative, as part of the 10th embodiment, DUR-TBA is in crystalline form A and is characterized by at least six X-ray powder diffraction peaks at 2Θ angles selected from 7.3°, 8.5°, 8.7°, 10.3°, 12.7°, 19.5°, and 21.4°. In the 10th embodiment as part of the 10th embodiment, it is in crystalline form A and is characterized by X-ray powder diffraction peaks at 2Θ angles selected from 7.3°, 8.5°, 8.7°, 10.3°, 12.7°, 19.5°, and 21.4°. In another alternative, as part of the 10th embodiment, DUR-TBA is in crystalline form A and is characterized by at least three, at least four, at least five, at least six, or at least seven X-ray powder diffraction peaks at the 2Θ angles listed in Table 15.

[0032]

[0043] In the 11th embodiment, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 95 wt%, or at least 99 wt% of the DUR-TBA crystal form A is in the single crystal form, and optionally, in the 10th embodiment, it is characterized by the XRPD peaks listed above. Alternatively, as part of the 11th embodiment, the DUR-TBA crystal form A is optionally present in a pure crystal form characterized by the XRPD peaks listed above in the 10th embodiment.

[0033]

[0044] In the 12th embodiment, the DUR-TBA crystal form A is characterized by an X-ray powder diffraction pattern that is substantially similar to FIG. 1.

[0045] In the 13th embodiment, the salt of formula I has the structural formula:

[0034]

Chemical formula

[0035] and is referred to herein as durlobactam calcium salt (DUR-Ca).

[0046] In the 14th embodiment, the salt of formula I or (DUR-Ca) is crystalline.

[0036]

[0047] In the 15th embodiment, DUR-Ca is in crystalline form B. Alternatively, as part of the 15th embodiment, DUR-Ca is in crystalline form B and is characterized by at least three X-ray powder diffraction peaks at 2Θ angles selected from 9.6°, 12.5°, 12.7°, 14.1°, 16.5°, 16.6, 22.5°, and 24.6°. In another alternative, as part of the 15th embodiment, DUR-Ca is in crystalline form A and is characterized by at least four X-ray powder diffraction peaks at 2Θ angles selected from 9.6°, 12.5°, 12.7°, 14.1°, 16.5°, 16.6, 22.5°, and 24.6°. In another alternative, as part of the 15th embodiment, DUR-Ca is in crystalline form A and is characterized by at least five X-ray powder diffraction peaks at 2Θ angles selected from 9.6°, 12.5°, 12.7°, 14.1°, 16.5°, 16.6, 22.5°, and 24.6°. In another alternative, as part of the 15th embodiment, DUR-Ca is in crystalline form A and is characterized by at least six X-ray powder diffraction peaks at 2Θ angles selected from 9.6°, 12.5°, 12.7°, 14.1°, 16.5°, 16.6, 22.5°, and 24.6°. In another alternative, as part of the 15th embodiment, DUR-Ca is in crystalline form A and is characterized by X-ray powder diffraction peaks at 2Θ angles selected from 9.6°, 12.5°, 12.7°, 14.1°, 16.5°, 16.6, 22.5°, and 24.6°. In another alternative, as part of the 15th embodiment, DUR-Ca is in crystalline form B and is characterized by at least three, at least four, at least five, at least six, or at least seven X-ray powder diffraction peaks at the 2Θ angles listed in Table 17.

[0037]

[0048] In the 16th embodiment, the DUR-Ca crystal form B is at least 70 wt% in single crystal form, at least 80 wt% in single crystal form, at least 90 wt% in single crystal form, at least 95 wt% in single crystal form, or at least 99 wt% in single crystal form, and optionally, in the 15th embodiment, is characterized by the XRPD peaks listed above. Alternatively, as part of the 16th embodiment, the DUR-Ca crystal form A is optionally present in a pure crystal form characterized by the XRPD peaks listed above in the 16th embodiment.

[0038]

[0049] In the 17th embodiment, the DUR-Ca crystal form B is characterized by an X-ray powder diffraction pattern that is substantially similar to FIG. 5.

[0050] In the 18th embodiment, DUR-Ca is in crystalline form A. Alternatively, as part of the 18th embodiment, DUR-Ca is in crystalline form A and is characterized by at least three X-ray powder diffraction peaks at 2Θ angles selected from 7.8°, 9.0°, 11.9°, 13.4°, 16.2°, 19.5°, 20.5°, and 25.0°. In another alternative, as part of the 18th embodiment, DUR-Ca is in crystalline form A and is characterized by at least four X-ray powder diffraction peaks at 2Θ angles selected from 7.8°, 9.0°, 11.9°, 13.4°, 16.2°, 19.5°, 20.5°, and 25.0°. In another alternative, as part of the 18th embodiment, DUR-Ca is in crystalline form A and is characterized by at least five X-ray powder diffraction peaks at 2Θ angles selected from 7.8°, 9.0°, 11.9°, 13.4°, 16.2°, 19.5°, 20.5°, and 25.0°. In another alternative, as part of the 18th embodiment, DUR-Ca is in crystalline form A and is characterized by at least six X-ray powder diffraction peaks at 2Θ angles selected from 7.8°, 9.0°, 11.9°, 13.4°, 16.2°, 19.5°, 20.5°, and 25.0°. In another alternative, as part of the 18th embodiment, DUR-Ca is in crystalline form A and is characterized by X-ray powder diffraction peaks at 2Θ angles selected from 7.8°, 9.0°, 11.9°, 13.4°, 16.2°, 19.5°, 20.5°, and 25.0°. In another alternative, as part of the 18th embodiment, DUR-Ca is in crystalline form A and is characterized by at least three, at least four, at least five, at least six, or at least seven X-ray powder diffraction peaks at the 2Θ angles listed in Table 18.

[0039]

[0051] In the 19th embodiment, the DUR-Ca crystal form A is at least 70 wt% in single crystal form, at least 80 wt% in single crystal form, at least 90 wt% in single crystal form, at least 95 wt% in single crystal form, or at least 99 wt% in single crystal form, and optionally, in the 15th embodiment, is characterized by the XRPD peaks listed above. Alternatively, as part of the 19th embodiment, the DUR-Ca crystal form A optionally exists in a pure crystal form characterized by the XRPD peaks listed above in the 16th embodiment.

[0040]

[0052] In the 20th embodiment, the DUR-Ca crystal form A is characterized by an X-ray powder diffraction pattern that is substantially similar to FIG. 7.

[0053] In the 21st embodiment, the salt of DUR-Ca is in crystalline form C. Alternatively, as part of the 21st embodiment, DURCa is in crystalline form C and is characterized by at least three X-ray powder diffraction peaks at 2Θ angles selected from 7.0°, 9.5°, 12.1°, 16.1°, 16.9°, 19.7°, 20.3°, and 26.9°. In another alternative, as part of the 21st embodiment, DUR-Ca is in crystalline form C and is characterized by at least four X-ray powder diffraction peaks at 2Θ angles selected from 7.0°, 12.2°, 16.1°, 16.9°, 19.7°, 20.3°, and 26.9°. In another alternative, as part of the 21st embodiment, DUR-Ca is in crystalline form C and is characterized by at least five X-ray powder diffraction peaks at 2Θ angles selected from 7.0°, 12.2°, 16.1°, 16.9°, 19.7°, 20.3°, and 26.9°. In another alternative, as part of the 21st embodiment, DUR-Ca is in crystalline form C and is characterized by at least six X-ray powder diffraction peaks at 2Θ angles selected from 7.0°, 12.2°, 16.1°, 16.9°, 19.7°, 20.3°, and 26.9°. In another alternative, as part of the 21st embodiment, DUR-Ca is in crystalline form C and is characterized by X-ray powder diffraction peaks at 2Θ angles selected from 7.0°, 12.2°, 16.1°, 16.9°, 19.7°, 20.3°, and 26.9°. In another alternative, as part of the 21st embodiment, DUR-Ca is in crystalline form C and is characterized by at least three, at least four, at least five, at least six, or at least seven X-ray powder diffraction peaks at the 2Θ angles listed in Table 20.

[0041]

[0054] In the 22nd embodiment, the DUR-Ca crystal form C is at least 70 wt% in single crystal form, at least 80 wt% in single crystal form, at least 90 wt% in single crystal form, at least 95 wt% in single crystal form, or at least 99 wt% in single crystal form, and optionally, in the 18th embodiment, is characterized by the XRPD peaks listed above. Alternatively, as part of the 22nd embodiment, the DUR-Ca crystal form C is present in a pure crystal form that is optionally, in the 18th embodiment, characterized by the XRPD peaks listed above.

[0042]

[0055] In the 23rd embodiment, the DUR-Ca crystal form C is characterized by an X-ray powder diffraction pattern that is substantially similar to FIG. 10.

[0056] In the 24th embodiment, the salt of DUR-Ca is in crystalline form F. Alternatively, as part of the 24th embodiment, DUR Ca is in crystalline form F and is characterized by at least three X-ray powder diffraction peaks at 2Θ angles selected from 9.5°, 11.3°, 12.0°, 14.0°, 17.0°, 19.0°, and 19.5°. In another alternative, as part of the 24th embodiment, DUR-Ca is in crystalline form F and is characterized by at least four X-ray powder diffraction peaks at 2Θ angles selected from 9.5°, 11.3°, 12.0°, 14.0°, 17.0°, 19.0°, 22.3°, and 24.2°. In another alternative, as part of the 24th embodiment, DUR-Ca is in crystalline form F and is characterized by at least five X-ray powder diffraction peaks at 2Θ angles selected from 9.5°, 11.3°, 12.0°, 14.0°, 17.0°, 19.0°, 22.3°, and 24.2°. In another alternative, as part of the 24th embodiment, DUR-Ca is in crystalline form F and is characterized by at least six X-ray powder diffraction peaks at 2Θ angles selected from 9.5°, 11.3°, 12.0°, 14.0°, 17.0°, 19.0°, 22.3°, and 24.2°. In another alternative, as part of the 24th embodiment, DUR-Ca is in crystalline form F and is characterized by X-ray powder diffraction peaks at 2Θ angles selected from 9.5°, 11.3°, 12.0°, 14.0°, 17.0°, 19.0°, 22.3°, and 24.2°. In another alternative, as part of the 24th embodiment, DUR-Ca is in crystalline form F and is characterized by at least three, at least four, at least five, at least six, or at least seven X-ray powder diffraction peaks at the 2Θ angles listed in Table 21.

[0043]

[0057] In the 25th embodiment, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 95 wt%, or at least 99 wt% of the DUR-Ca crystal form F is in the single crystal form, and optionally, in the 25th embodiment, it is characterized by the XRPD peaks listed above. Alternatively, as part of the 25th embodiment, the DUR-Ca crystal form F is optionally present in a pure crystal form characterized by the XRPD peaks listed above in the 25th embodiment.

[0044]

[0058] In the 26th embodiment, the DUR-Ca crystal form F is characterized by an X-ray powder diffraction pattern that is substantially similar to FIG. 13.

[0059] Also provided herein is a method for preparing DUR-Ca, the method including the step of reacting DUR-TBA with calcium chloride in a solvent such as ethanol to obtain DUR-Ca. In one aspect, the DUR-Ca form according to the disclosed method is crystal form A or B or C or F described herein (e.g., any one of the 15th to 26th embodiments).

[0045]

[0060] Also provided herein is a method for preparing DUR-TEA, the structural formula

[0046]

Chemical formula

[0047] A method is also provided that includes reacting a hydroxyurea compound with a sulfur trioxide complex (e.g., sulfur trioxide pyridine complex, sulfur trioxide triethylamine complex, sulfur trioxide N,N-dimethylformamide complex, etc.) and triethylamine to form DUR-TEA. In one aspect, the DUR-TEA synthesized by the disclosed method is in crystalline form A described herein (e.g., any one of Embodiments 4 to 6). In one aspect, the sulfur trioxide complex used in the preparation of DUR-TEA is a sulfur trioxide pyridine complex. In one aspect, the reaction of the hydroxyurea compound with the sulfur trioxide pyridine complex and trimethylamine occurs in a solvent such as acetonitrile. In one aspect of the above method for preparing DUR-TEA, the method further includes the step of precipitating a triethylammonium salt from the solution using a co-solvent such as acetone.

[0048]

[0061] A method for preparing DUR-TBA is also provided that includes reacting DUR-TEA with tetrabutylammonium hydrogen sulfate and sodium dihydrogen phosphate to form DUR-TBA. In one aspect, DUR-TBA and / or DUR TEA are in crystalline form A described herein (e.g., any one of Embodiments 4 to 6 and / or any one of Embodiments 9 to 12). In one aspect of the above method for preparing DUR-TBA, the method further includes the step of precipitating a tetrabutylammonium salt from a solvent such as acetone.

[0049]

[0062] A method for preparing DUR-Ca is also provided, which includes the step of reacting DUR-TBA with calcium chloride to form DUR-Ca. In one aspect, DUR-TBA and / or DUR-Ca are in the crystal form B described herein (for example, any one of the embodiments of paragraphs 9 to 12 and / or paragraphs 15 to 17). In one aspect, DUR-Ca is in the crystal form A described herein (for example, any one of the embodiments of paragraphs 18 to 20). In one aspect, DUR-Ca is in the crystal form C described herein (for example, any one of the embodiments of paragraphs 21 to 23). In one aspect, DUR-Ca is in the crystal form F described herein (for example, any one of the embodiments of paragraphs 24 to 26). In one aspect of the above method for preparing DUR-Ca, the reaction is completed in a solvent such as ethanol.

[0050]

[0063] A method for preparing DUR-Na is also provided, which includes the step of reacting either DUR-TEA or DUR-TBA with a sodium ion exchange resin to form DUR-Na. In one aspect, DUR-TEA and / or DUR TBA are in the crystal form A described herein (for example, any one of the embodiments of paragraphs 3 to 6 and / or paragraphs 9 to 12).

[0051]

[0064] A method for preparing DUR-Na is also provided, which includes the step of reacting DUR-Ca with sodium carbonate to form DUR-Na. In one aspect, DUR-Ca is in the crystal form B described herein (for example, any one of the embodiments of paragraphs 15 to 17). In one aspect, DUR-Ca is in the crystal form A described herein (for example, any one of the embodiments of paragraphs 18 to 20). In one aspect, DUR-Ca is in the crystal form C described herein (for example, any one of the embodiments of paragraphs 21 or 23). In one aspect, DUR-Ca is in the crystal form F described herein (for example, any one of the embodiments of paragraphs 24 to 26).

[0052]

[0065] The following examples are intended to be illustrative and are not intended to limit the scope of the disclosure in any way.

Examples

[0053] Illustrative

[0054]

Table 1

[0055]

Table 2

[0056]

Table 3

[0057]

[0069] Experimental data of XRPD method and DSC method

[0070] XRPD method for DUR-TBA, DUR-Ca Form B, and Form F The analysis is performed by default from 2θ = 3° to 50°. X-ray powder diffraction analysis was carried out in transmission mode unless otherwise stated. The sample (a few milligrams) is introduced into a 1-mm diameter glass capillary in a slightly crushed state to avoid preferred orientation. The capillary is sealed to avoid contact with air. The analysis is performed in transmission mode on a PANalytical Empyrean diffractometer using a focusing X-ray mirror equipped with divergence slits and anti-scatter slits (aperture 0.5°). This diffractometer is equipped with a copper anticathode tube (wavelength λKα1 = 1.54060 Å / Kα2 = 1.54443 Å) and a PIXcel 1D detector with a 7.5-mm anti-scatter slit. The calibration of the analytical instrument is checked prior to each analysis batch according to the quality system. This table summarizes the experimental conditions of the measurements.

[0058]

Table A

[0059]

[0071] XRPD Method for DUR-TEA, DUR-Ca Forms A and C Equipment: Bruker D8 Advance X-ray powder diffractometer Method parameters: Diffractometer settings: Goniometer type: theta / theta Sample stage: standard rotating stage Tube parameters: voltage 40 kV, current 40 mA Scan parameters Rotation speed: 30° / min Scan angle: 3 。 ~40 。 (2θ) Scan step: 0.02 。 (2θ) Scan speed: 0.1 s / step Sample preparation: Take an appropriate amount of the test sample in the sample pan and flatten it with a spoon. Then, test it with the above parameters.

[0060]

[0072] DSC Method A (for DUR-TBA, DUR-TEA, DUR-Ca Crystal Forms A and C) Equipment: TA DSC Q200 Method parameters: Sensor: DSC (differential scanning calorimetry) Crucible: gold, 25 μL, open lid Temperature increase: 10 °C / min from 20 °C to 450 °C Sample purge flow rate (N2): 50 ml / min Pan: pinhole pan Mode: standard Heating rate: 10 K / min Sample preparation: Weigh 1 - 3 mg of the sample into a pinhole pan, gently shake to flatten the sample surface, and test the usage method.

[0061]

[0073] TGA Method A (for DUR-TBA, DUR-TEA, DUR-Ca Crystal Forms A and C) Apparatus: TA TGA Q500 Method parameters: Sensor: TGA (Thermogravimetric analysis) Crucible: Aluminum, 25 μL, open lid Temperature increase: 30 °C to 300 °C at 10 °C / min

[0062] Sample purge flow rate (N 2 ): Balance part is 40 ml / min, sample is 60 ml / min Pan: Open aluminum Mode: TGA 1000 °C Sample preparation: Put an appropriate amount of sample into the weighed aluminum pan that has been blank measured, automatically weigh it, insert the pan into the TGA furnace and follow the method

[0063]

[0074] TGA and DSC method B (for DUR-Ca crystal forms B and F) Apparatus: STA 449C Jupiter Netzsch Method parameters: Sensor: TGA / DSC (Thermogravimetric analysis / Differential scanning calorimetry) Crucible: Aluminum, 25 μL, open lid Sample purge flow rate: Nitrogen, 50 mL / min Temperature: 25 °C to 400 °C Heating rate: 4 K / min Sample preparation: Weigh 4 - 6 mg of sample with the lid open, gently shake to flatten the sample surface, and test the usage method

[0064]

[0075] Overview of crystal salts

[0076] As described above, conventional processes for generating DUR-Na involve the use of phosphonium salts, which are then passed through an ion exchange resin to form DUR-Na. The problems with this method are that the phosphonium salts are not crystalline (difficult to handle), have a purity of less than 95%, and are not suitable for large-scale production. To solve this problem, salt screening of DUR was carried out, and crystalline salts with acceptable properties that can be used as alternatives to the phosphonium salts of DUR used in the conventional process were identified. See, for example, Example 10 of WO2013 / 150296.

[0065]

[0077] Since DUR is easily decomposed by free acid, the salt screening was carried out using salt exchange with crystalline DUR-TBA salt, which is a crystalline anhydride and soluble in most solvents.

[0066]

[0078] Amorphous salts were first prepared on a small scale from six counterions (N-methyl-D-glucamine, tromethamine, NH 4 + , Zn 2+ , Na + , and Ca 2+ ) using the ion exchange resin method, and then lyophilized to isolate XRPD amorphous solids. The ion exchange method was very time-consuming and had a low yield, and many salts contained residual TBA even after passing through the ion exchange column multiple times.

[0067]

[0079] In the concentrated crystallization screening of amorphous salts, no crystalline substances were found except for DUR-Ca. DUR-TBA salt and six calcium salts (CaCl 2 , CaBr 2 , Ca(BF 4 ) 2 , Ca(OAc) 2, an attempt was made to form DUR-Ca via salt metathesis in a slurry reaction with (calcium D-gluconate and calcium citrate), which was very time-consuming and costly to scale up, and an alternative method to ion exchange resins was found. Solids isolated from most counterions were composed of starting materials and were found to be amorphous. Finally, after extensive experiments, salt exchange from TBA to Ca was found to function well in EtOH where DUR-TBA and CaCl 2 are soluble and DUR-Ca crystallizes from the solution. Further experiments and extensive polymorph screening were carried out, and two polymorphs were identified and confirmed. Crystal form A is initially formed and unstable in a particular solvent system and is converted to the more stable crystal form C.

[0068]

[0080] Also, the TEA salt of DUR (DUR-TEA) was accidentally found to be an excellent crystalline solid. However, efforts to find crystalline salts with other amines were unsuccessful. The pyridine salt is not stable and cannot be isolated as a stable solid. Several other amine salts, such as tromethamine, ammonia, N-methyl-D-glucamine, meglumine, lysine, choline, ornithine, etc., which are considered useful as pharmaceutically suitable salts, were found to be non-crystalline. Crystallization experiments were carried out in many different solvents or solvent mixtures, such as evaporation, room temperature slurry, vapor stress at room temperature, and temperature cycling, using crystalline DUR-Ca salt, DUR-TBA salt, and DUR-TEA salt as seeds. Under all conditions, no crystalline solid was formed.

[0069]

[0081] The technology described in this specification is further illustrated by the following examples, which should not be construed as further limitations. It should be understood that the present invention is not limited in any way to the specific methods, protocols, and reagents described herein and can therefore be modified. The technical terms used herein are for the sole purpose of describing specific embodiments and are not intended to limit the scope of the present invention, which is defined only by the claims.

[0070]

[0082] Detailed conditions

[0083] Ion exchange resin experiment

[0084] Six salts were generated from DUR-TBA (see the following synthesis) using ion exchange resins, and these salts included sodium, calcium, ammonium, zinc, tromethamine, and N-methyl-D-glucamine. The experiments were carried out on a scale of 30 - 350 mg. A solution of DUR-TBA in water was prepared and eluted through a column containing 74 - 274 molar equivalents of Amberlyst15 (wet)-H or Dowex 50WX2 ion exchange resin charged with the desired counterion. The solution was slowly eluted through the column under gravity. In some cases, the resin was passed through twice to complete the exchange. The column was washed with water, and the combined eluate was frozen with liquid nitrogen or dry ice and lyophilized to obtain the salts as solids. The experiments were first carried out on a small scale and, if successful, repeated on a larger scale.

[0071]

[0085] Generally, the salt conversion process was very time-consuming because elution was carried out under gravity and the elution rate was kept slow to improve the purity and yield of the product. However, many salts still contained residual TBA even after passing through the resin column multiple times, and there seemed to be particular problems with divalent counterions. In addition, the Dowex resin seemed to promote decomposition. The lyophilization of sodium salts and N-methyl-D-glucamine salts had problems because the frozen solution was thawed several times during lyophilization. Therefore, it was necessary to further dilute them with water, which also increased the lyophilization time.

[0072]

[0086] Sodium salts, calcium salts, ammonium salts, and zinc salts could be scaled up for crystallization screening, but tromethamine and N-methyl-D-glucamine decomposed during scaling up. The lyophilized salts were composed of XRD amorphous powders.

[0073]

[0087] Salt metathesis experiments

[0088] The salt metathesis experiments were completed with eight types of counterions (choline, lysine, magnesium, N-methyl-D-glucamine (meglumine), ornithine, potassium, tromethamine, and calcium). The experiments were carried out on a 20 - 40 mg scale. A 25 mg / mL solution of the duryllobacterium tetrabutylammonium salt was prepared in various solvents and added to small vials containing 1 - 2 molar equivalents of the cocrystal former. A stir bar was added to each vial, which was then purged with nitrogen and sealed. The reactants were stirred in the dark for up to 7 days.

[0074] Choline salt experiments

[0089] The salt metathesis slurry was set up on a scale of approximately 30 mg. The reactants were stirred for several days, but only the presence of choline chloride was shown in the samples, as shown in Table 4 below. The reaction mixture was dried under a nitrogen stream, and some small grains of gel and birefringent material were obtained. Analysis of these samples showed that they were a mixture of choline chloride and an amorphous substance. An attempt was made to dry the gel at room temperature under vacuum for several days, but no improvement in crystallinity was visually observed. The inability to form choline salts may be related to the low solubility of choline salts in the solvents used.

[0075]

Table 4

[0076] Lysine salt experiment

[0090] Attempts were made to form Durobacterium lysine salts by salt metathesis slurry and crash precipitation experiments using lysine hydrochloride. Since lysine hydrochloride has low solubility in most organic solvents, the reaction was carried out in polar protic solvents. The formation of lysine salts was unsuccessful in the crash precipitation experiments. As shown in Table 5 below, analysis by XRPD showed that lysine hydrochloride was obtained in most experiments.

[0077]

Table 5

[0078] Magnesium salt metathesis experiment

[0091] Attempts were made to form Durobacterium magnesium salts by salt metathesis slurry and crash precipitation experiments using magnesium sulfate, magnesium chloride, or magnesium stearate. As shown in Table 6 below, analysis by XRPD showed that MgCl 2 , MgSO 4 , or magnesium stearate was obtained in most experiments.

[0079]

Table 6

[0080] N-Methyl-D-glucamine salt experiment

[0092] The formation of durlobactam N-methyl-D-glucamine salt was attempted by salt metathesis slurry and crash precipitation experiments using N-methyl-D-glucamine hydrochloride. As shown in Table 7 below, NMDG HCl was obtained in all experiments.

[0081]

Table 7

[0082] Ornithine salt experiment

[0093] The formation of durlobactam ornithine salt was attempted by salt metathesis slurry and crash precipitation experiments using ornithine hydrochloride. As shown in Table 8 below, ornithine HCl was obtained in most experiments.

[0083]

Table 8

[0084] Potassium salt experiment

[0094] The formation of durlobactam potassium salt was attempted by salt metathesis slurry and crash precipitation experiments using either potassium acetate or potassium chloride. As shown in Table 9 below, gels were obtained in most experiments.

[0085]

Table 9

[0086] Tromethamine salt metathesis experiment

[0095] The formation of durlobactam tromethamine salt was attempted by salt metathesis slurry and crash precipitation experiments using tromethamine hydrochloride. As shown in Table 10 below, tromethamine HCl was obtained in most experiments.

[0087]

Table 10

[0088] Calcium salt metathesis experiment

[0096] Using various calcium salts, the formation of Durobacterium calcium salts was attempted with a metathesis slurry. In most of the experiments, as shown in Table 11 below, no crystalline substances or calcium salt starting materials were obtained. Ca(BF 4 ) 2 yielded various crystal structures, but these were usually disordered and not suitable for scale-up procedures. From this screening, only CaCl in EtOH or IPA 2 provided uniform and scalable crystallization.

[0089]

Table 11-1

[0090]

Table 11-2

[0091]

[0097] Crystallization screening

[0098] In the metathesis screening, almost no successful salts were obtained and no crystalline substances were obtained either. Therefore, only the sodium salts, calcium salts, ammonium salts, and zinc salts prepared by ion exchange (Method 1) were tested for crystallinity as described below.

[0092] Crystallization screening of Durobacterium ammonium salt

[0099] For Durobacterium ammonium salt, various crystallization experiments were carried out, including evaporation, room temperature slurry, slurry with DUR-TBA seeded, vapor stress at room temperature, and temperature cycling.

[0093]

[0100] The screening method is as follows.

[0101] Low-speed evaporation - Solutions of the dulurobactam salts were prepared in each solvent. The solutions were evaporated in vials under a nitrogen stream in a draft at room temperature. The resulting solids were analyzed by XRPD.

[0094]

[0102] Slurry experiment - A sufficient amount of dulurobactam salt was added to a predetermined solvent until a solid that did not dissolve remained at the specified temperature. The vial was sealed, the slurry was maintained at the selected temperature, and shaken and stirred for up to 14 days. The samples were examined daily for crystallinity with a polarized light microscope.

[0095]

[0103] Vapor stress - An aliquot of the dulurobactam salt was weighed into unused glass vials. These vials were placed without caps into a large vial containing 500 μL of the selected solvent. The large vial was capped and stored at 20 or 40 °C. The samples were visually inspected with a polarized light microscope.

[0096]

[0104] Temperature cycling - The test solvent (1 mL) was added to a sample of the dulurobactam salt (about 3 - 10 mg) at room temperature, and the following temperature program was run 5 - 16 cycles using a Clarity crystallization station:

[0105] Heat from 0 °C to 20 °C at 0.5 °C / min

[0106] Hold at 20 °C for 1 minute

[0107] Cool to 0 °C at 0.1 °C / min

[0108] Hold at 0 °C for 1 minute

[0109] Without stirring

[0110] Seeding experiment - The slurry of the dulurobactam salt was seeded with crystalline salt DUR-TBA or crystalline salt DUR-Ca. The substances were slurried at 20 or 60 °C for several days, and the degree of crystallization was examined with a polarized light microscope.

[0097]

[0111] Ultrasonic treatment - A sufficient amount of Durobacterium salt was added to a selected solvent until undissolved solids remained. The mixture was sonicated at 30% intensity using a Cole-Parmer 130W ultrasonic processor and a pulse program. If the solids did not precipitate at room temperature, the sample was stored at 4 °C for 18 hours. All solids recovered in these experiments were analyzed using XRPD.

[0098]

[0112] The results of various experiments are detailed in Table 12 below, indicating that no crystalline substances were formed by any method.

[0099]

Table 12

[0100] Crystallization screening of Durobacterium calcium salt (DUR-Ca)

[0113] The first slurry experiment was completed using Durobacterium calcium salt. The results of various experiments are detailed in Table 13 below, indicating that crystalline substances were formed only when ethanol or EtOAc was used. A more comprehensive crystallization screening was later performed, and the results are shown in Table 13.

[0101]

Table 13

[0102] Crystallization screening of Durobacterium zinc salt

[0114] The slurry and vapor stress experiments were completed using Durobacterium zinc salt. The results of various experiments are detailed in Table 14 below, indicating that no crystalline substances were formed by any method.

[0103]

Table 14

[0104]

[0115] Despite a wide range of salt screening methods, crystallization methods, and other conditions that include metal salts (calcium, zinc, magnesium, and potassium) and amines (tris, ornithine, N-methyl-D-glucamine, lysine, choline, and ammonia), it was found that only calcium salts are scalable and crystalline substances. In addition to calcium salts, triethylamine salts and tetrabutylammonium salts were also found to be scalable and crystalline, which will be discussed in subsequent examples.

[0105]

[0116] Preparation and Characterization of the Durobactam Tetrabutylammonium Salt (DUR-TBA) Form A

[0117] Method 1

[0106]

Chem.

[0107]

[0118] To a solution of tert-butyl (3R,6S)-3-((tert-butoxycarbonyl)(hydroxy)amino)-6-carbamoyl-5-methyl-3,6-dihydropyridine-1(2H)-carboxylate (for the synthesis of this compound, see WO2018 / 53215) (110 kg, 1.0 equivalent) and imidazole (40.65 kg, 2.0 equivalents) in DCM (634.5 kg, 4.3 V) at 0 ± 5 °C was added a solution of TBSCl in DCM (148 kg, 1.0 V) (58.5 kg, 1.3 equivalents). The reaction mixture was stirred at 0 °C for at least 16 h and washed three times with water (first with 555 kg of water, and then the second and third times with 333 kg of water each). After the third wash, the organic phase was distilled to remove residual water. DCM (5 V) was added and distilled. This DCM addition / distillation was repeated until the water content of the organic phase was ≤ 0.5% by KF. HPLC showed a purity of 99.5%. The solution was used without further purification.

[0108]

[0119] To the above solution of tert-butyl (3R,6S)-3-((tert-butoxycarbonyl)((tert-butyldimethylsilyl)oxy)amino)-6-carbamoyl-5-methyl-3,6-dihydropyridine-1(2H)-carboxylate in DCM at 25 ± 5 °C, ZnBr 2 (269.1 kg, 4.0 eq) was added portionwise. After addition, the solution was stirred for 24 h. Then, a solution of NH 4 Cl (16 eq) / NH 4 OH (16 eq) in water (prepared by mixing 255.5 kg of NH 4 Cl and 325 kg of 25% NH 4 OH in 1450 kg of water) was added. The mixture was stirred at 10 ± 5 °C for at least 2 h and then left to stand for at least 1 h.

[0109]

[0120] The organic phase was transferred to a solution of NH 4 Cl (10 eq) / NH 4 OH (10 eq) in water (prepared by mixing 160 kg of solid NH 4 Cl and 203.5 kg of 25% NH 4 OH in 1450 kg of water). The mixture was stirred at 20 °C ± 5 °C for at least 1 h. Then, the mixture was left to stand for at least 30 min.

[0110]

[0121] The organic phase was transferred to an NH 4 Cl 2 % w / V solution (prepared in advance by mixing 58 kg of solid NH 4 Cl and 2901 kg of water). The mixture was stirred at 20 °C ± 5 °C for at least 30 min and then left to stand for at least 30 min. The organic phase was washed 5 times with water at 20 °C ± 5 °C. Next, 8 V of DCM was distilled off at atmospheric pressure. 4 V of ethyl acetate was charged and the solvent was distilled off. This process was repeated once more.

[0111]

[0122] At the end of the distillation, ethyl acetate (4V) was charged again to form (2S,5R)-5-(((tert-butyldimethylsilyl)oxy)amino)-3-methyl-1,2,5,6-tetrahydropyridine-2-carboxamide in the ethyl acetate solution. HPLC showed a purity of 96.3%. The solution was used without further purification.

[0112]

[0123] To a solution of (2S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-1,2,5,6-tetrahydropyridine-2-carboxamide in EtOAc, additional EtOAc (filled up to 30V), water (83 kg, 1V), and DIEA (150 kg, 4.0 equivalents) were added. The solution was cooled to 0 °C, and a solution of triphosgene (30 kg, 0.33 equivalent) in EtOAc (261 kg, 3.5V) was added over 4 hours. The solution was warmed to room temperature and stirred for 5 hours. Then, the reaction mixture was washed twice with water (10V), and then with saturated NaCl solution (5V). The organic phase was concentrated, and 27V of ethyl acetate was distilled off. 10V of n-heptane was refilled, and then 8 - 9V was distilled under vacuum. After distillation, the mixture was cooled to 20 ± 5 °C, then the solid was filtered and washed twice with a 1V ethyl acetate / heptane (1 / 10) mixture. The crude product was slurried with water (4V), filtered, washed with water (1V), and dried at 30 ± 5 °C to obtain (2S,5R)-6-((tert-butyldimethylsilyl)oxy)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide. HPLC showed a purity of 99.9%.

[0113]

[0124] A solution of (2S,5R)-6-((tert-butyldimethylsilyl)oxy)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (32.2 kg, 1.0 eq) in EtOAc (130.7 kg, 4.5 V) at 5 ± 5 °C was added dropwise with a solution of HF·Py (19.2 kg, 16.4% HF, 1.5 eq) in EtOAc. The addition apparatus was rinsed with EtOAc (0.87 kg). After the addition, the reaction mixture was warmed to 25 ± 5 °C and stirred for 4 h. The precipitate was collected and washed with EtOAc (29.58 kg, 1.0 V). The filter cake was added to EtOAc (59.16 kg, 2.0 V), stirred for at least 2 h, filtered, and washed with ethyl acetate (29.58 kg, 1.0 V). HPLC indicated a purity of 100%. The solid was dried at 20 ± 5 °C and used in the next step without further purification.

[0114]

[0125] To a solution of (2S,5R)-6-hydroxy-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (36 kg, 1 eq) in acetonitrile (74 kg, 94.1 L, 2.6 V) at 15 ± 2 °C was added SO 3 Py (46.5 kg, 1.6 eq) portionwise, followed by addition of TEA (29.5 kg, 1.6 eq). After the addition, the TEA addition line was rinsed with acetonitrile (0.4 V) and charged to the reaction mixture. The reaction mixture was stirred until the starting material was consumed (about 5 h).

[0115]

[0126] The reaction mixture was cooled to 3 ± 3 °C and slowly added to a pre-prepared cold solution (3 °C) of Bu 4 NHSO 4 (62.0 kg, 1.05 eq) and NaH 2 PO 4 -H 2 O (26.5 kg, 1.05 eq) in water (360 kg, 10 V). The resulting mixture was stirred at 3 ± 3 °C for at least 4 h, warmed to 20 ± 5 °C, and extracted with DCM (238.5 kg, 180 L, 5 V).

[0116]

[0127] The organic phase was isolated. The aqueous phase was extracted with DCM (238.5 kg, 5V). The combined organic phases were washed with a solution of NaH 2 PO 4· H 2 O (7.6 kg, 0.3 eq) in water (180 kg, 5V) and concentrated to approximately 5V. Acetone (853 kg, 1080 L, 30V) was added in portions. The resulting mixture was concentrated to approximately 5V. The solvent exchange with acetone (853 kg, 1080 L, 30V) was repeated one more time.

[0117]

[0128] EtOAc (368.0 kg, 408 L, 4.6V, first portion, precooled to -5 ± 5 °C) and crystalline tetrabutylammonium salt of the dulurobacterium seed crystal (360 g, 1 wt%) were added. The reaction mass was stirred at 10 ± 3 °C for 1 hour, cooled to -5 ± 3 °C over 3 - 4 hours, stirred for at least 2 hours, and additional EtOAc (368.0 kg, 408 L, 4.6V, second portion, precooled to -5 ± 5 °C) was added. The suspension was stirred at -5 ± 5 °C for 6 hours. The solid was collected by filtration, washed with EtOAc (2 x 130 kg (4V)) and washed with n - heptane (2 x 93 kg, 3.8V). The solid was dried by blowing nitrogen over it on the filter for at least 48 - 72 hours. HPLC showed a purity of 100.0%.

[0118]

[0129] 1 H - NMR δ (400 MHz, DMSO - D 6 ), δ 7.79 (1H, s, NH 2 of 1H), 7.32 (1H, s, NH 2 of 1H), 6.05 (1H, brs, CH), 4.09 (1H, s, CH), 4.02 (1H, s, CH), 3.68 (1H, m, 1H of cyclic CH 2 ), 3.20 (8H, m, 4x CH 2 ), 3.07 (1H, m, 1H of cyclic CH 2 ), 1.61 (3H, s, CH 3 ), 1.56 (8H, m, 4xCH 2 ), 1.35 (8H, m, 4xCH​​​​​​​​​​​​​​​​​​​​2 ), 0.95 (12H, m, 4xCH 3 ) ppm。

[0119]

[0130] Method 2

[0131] To a solution of tetrabutylammonium chloride (93.0 g, 1.0 eq) in water at 0 °C (1.0 L, 10 V), DUR-Na (100.0 g, 1.0 eq, 334.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Then, DCM (500.0 mL, 5.0 V) was added to the reaction mixture and stirred for an additional 30 min. The layers were separated and the organic layer was collected. The aqueous layer was extracted once with DCM (500.0 mL, 5.0 V).

[0120]

[0132] The aqueous layer was cooled to 0 °C and additional tetrabutylammonium chloride (18.7 g, 0.2 eq) was added. The reaction mixture was stirred for 1 - 2 h. Then, DCM (500.0 mL, 5.0 V) was added to the reaction mixture and stirred for an additional 30 min. The layers were separated and the organic layer was collected. The aqueous layer was extracted once with DCM (500.0 mL, 5.0 V).

[0121]

[0133] The combined organic layers were concentrated to approximately 6.5 V. Acetone (3.0 L, 30.0 V) was added and the solution was concentrated to approximately 6.5 V. EtOAc (2.0 L, 20.0 V) was added and the solution was cooled to 0 °C, followed by the addition of additional EtOAc (4.0 L, 40.0 V). The solution was stirred at 0 °C for 18 h. The precipitated solid was collected, washed with EtOAc (200.0 mL, 2.0 V), and dried at 35 °C or below for 24 h.

[0122]

[0134] DUR-TBA crystalline form A was characterized by XRPD (Figure 1 and Table 15) and TGA and DSC (Figure 2). Peaks with relative intensity less than 1% are not reported.

[0123]

Table 15

[0124]

[0135] Preparation and Characterization of Duroctam Triethylamine Salt (DUR-TEA) Polymorph A

[0136] To a solution of (2S,5R)-6-hydroxy-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (243 g, 1 equiv) in acetonitrile (730 mL, 3V) at 10 °C, SO 3 Py (255 g, 1.3 equiv) was added portionwise, followed by TEA (163 g, 1.3 equiv). After the addition, the reaction mixture was stirred for at least 18 h until the starting material was consumed. Acetone (3.7 L, 15V) was added. The reaction mixture was cooled to -40 °C and the resulting mixture was stirred for at least 18 h. The solid was collected by filtration, washed with acetone / ACN (480 mL, 2V, 5 / 1 ratio), and dried under vacuum at 25 - 30 °C for at least 24 h. HPLC purity: 99.2%

[0137] 1 1H-NMR δ (400 MHz, DMSO-D 6 ), 1.20 (9H, m), 2.50 (3H, s), 3.12 (7H, m), 3.67 (1H, d), 4.01 (1H, m), 4.09 (1H, s), 6.05 (1H, m), 7.32 (1H, s), 7.79 (1H, s); 13 13C-NMR (400 MHz, DMSO-D 6 6) 9.12, 20.50, 46.28, 56.79, 66.07, 126.01, 135.48, 168.67, 170.43 ppm. IR(cm -1 ): 3442.19, 3333.79, 3070.15, 1775.26, 1691.35, 1328.65, 1274.34, 1240.85, 1159.49 1057.57, 1016.24, 753.72 593.113

[0138] DUR-TEA Polymorph A was characterized by XRPD (Figure 3 and Table 16) and TGA and DSC (Figure 4). Peaks with relative intensity less than 1% are not reported.

[0125]

Table 16

[0126]

[0139] Preparation and Characterization of the Durobacterium Calcium Salt (DUR-Ca) Form B

[0140] The inactivation reactor is charged with the following: anhydrous CaCl 2 (7.5 kg, 0.5 eq) and ethanol (442 kg, 8 V). The reaction mixture is stirred until completely dissolved at 20 °C ± 5 °C and then maintained at this temperature until used in the synthesis. The second inactivation reactor is continuously charged with the following: DUR-TBA (70 kg, 1 eq) and ethanol (276.5 kg, 5 V). The reaction mixture is brought to 20 °C ± 5 °C and stirred until dissolved at this temperature. Next, the calcium chloride solution (previously prepared) is added slowly over a minimum of 1 hour (through a filling vessel with a dip tube). At the end of the addition, the reactor used for the preparation of the calcium chloride solution is rinsed with ethanol (41.5 kg, 0.75 V) and then transferred to the synthesis reactor. The reaction mixture is maintained at 20 °C ± 5 °C for a minimum of 16 hours. At the end of the contact, the mixture is cooled to 0 °C ± 5 °C and maintained at this temperature for a minimum of 2 hours. The mixture is filtered and washed with ethanol (110.5 kg, 2 V) cooled to 0 °C ± 5 °C. The wet cake is Crystal B and contains up to 20% EtOH as a solvate. The wet DUR-Ca is first slurried with ethanol (276.5 kg, 5 V) at 20 °C ± 5 °C for at least 2 hours, filtered, and successively washed with ethanol (110.5 kg, 2 V) and then acetone (110 kg, 2 V) and dried (under vacuum at 35 °C with a nitrogen bleed) until the weight is constant before analysis. Up to this stage, the solid remains as Crystal B and contains EtOH and acetone as solvates.

[0127]

[0141] The DUR-Ca Crystal Form B was characterized by XRPD (Figure 5, Table 17) and TGA / DSC (Figure 6). Peaks with relative intensities less than 1% are not reported.

[0128]

Table 17-1

[0129] [Table 17-2]

[0130]

[0142] Preparation and characterization of dururobactam calcium salt (DUR-Ca) form A

[0143] Method A: CaCl in absolute EtOH (26.4 L, 10 V) 2 To a solution of DUR-TBA (282.5 g, 0.5 equiv.) in EtOH (13.2 L, 5 V) was added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred at 15 °C for 40 h. The reaction mixture was cooled to 0-5 °C and stirred for 4 h. The solid was collected by centrifugation and washed with EtOH (2 V). The wet cake was slurried in EtOH (6 V) at 25-30 °C for 3 h. The wet cake was collected by centrifugation and washed with EtOH (2 V). The wet solid was collected by centrifugation and slurried with EtOAc (12 V) at 25-30 °C for approximately 132 h. The solid was collected by centrifugation and dried in an oven until the residual solvent by H-NMR was ≦2.5% to give DUR-Ca. 2.04 kg, 98% purity by HPLC area %, 56% yield, crystalline form A.

[0131]

[0144] Method B: Add the following to a deactivation reactor: anhydrous CaCl 2Charge (7.5 kg, 0.5 equivalent) and ethanol (442 kg, 8 V). Stir the reaction mixture at 20 °C ± 5 °C until completely dissolved, and then maintain this temperature until used in the synthesis. Continuously charge the second inactivation reactor with the following: DUR-TBA (70 kg, 1 equivalent) and ethanol (276.5 kg, 5 V). Bring the reaction mixture to 20 °C ± 5 °C and stir until dissolved at this temperature. Next, slowly add the calcium chloride solution (previously prepared) over at least 1 hour (through a filling container with a dip tube). At the end of the addition, rinse the reactor used for the preparation of the calcium chloride solution with ethanol (41.5 kg, 0.75 V) and then transfer it to the synthesis reactor. The reaction mixture is maintained at 20 °C ± 5 °C for at least 16 hours. At the end of the contact, cool the mixture to 0 °C ± 5 °C and maintain at this temperature for at least 2 hours. Filter the mixture and wash with ethanol (110.5 kg, 2 V) cooled to 0 °C ± 5 °C. Wet DUR-Ca is first slurried with ethanol (276.5 kg, 5 V) at 20 °C ± 5 °C for at least 2 hours and filtered. Wash the cake successively with ethanol (110.5 kg, 2 V) and then with acetone (110 kg, 2 V). Charge wet DUR-Ca and acetone (384. Kg, 7 V) into the reactor and add 1 equivalent (2.43 kg) of water (PUW) at 20 °C ± 5 °C over at least 10 minutes. Heat the reaction mixture to reflux (56 °C ± 5 °C) and stir at this temperature for 30 minutes. Then, cool the mixture to 20 °C ± 5 °C over 1 hour, stir for 1 hour, filter, and wash with acetone (110 kg, 2 V). Dry DUR-Ca under vacuum at a maximum of ≦ 35 °C until the mass is constant to obtain crystalline form A, which usually contains about 1% - 5% acetone.

[0132]

[0145] 1 H-NMR (400 MHz, DMSO-D 6 ), δ 1.61 (3H, s), 3.06 (1H, m), 3.66 (1H, d), 4.02 (1H, m), 4.09 (1H, s), 6.05 (1H, m), 7.33 (1H, s), 7.80 (1H, s) ppm.

[0146] The DUR-Ca crystalline form A was characterized by XRPD (Figure 7 and Table 18), TGA (Figure 8), and DSC (Figure 9). Peaks with relative intensities less than 1% were not reported.

[0133]

Table 18

[0134]

[0147] Preparation and Characterization of Durulobacterium Calcium Salt (DUR-Ca) Form C

[0148] Method A

[0149] To a solution of CaCl 2 (0.6 equivalent) in anhydrous EtOH (5V), a solution of DUR-TBA (100 g, 1.0 equivalent) in EtOH (10V) was added while maintaining the reaction temperature at 20 ± 3 °C during the addition. After the addition was complete, the reaction mixture was stirred at 20 ± 3 °C for 16 hours. Then, the reaction was cooled to 0 ± 5 °C and stirred for at least 2 hours. The solid was collected by centrifuge and washed with EtOH (1.5V). The filter cake was added to EtOH (4V) and stirred at 25 ± 5 °C for at least 4 hours. The solid was collected by centrifuge, washed with EtOH (1.5V), and then washed with IPA (1.5V). The filter cake was added to a solution of IPOAc (4V) and water (0.7 equivalent) and stirred at 25 ± 5 °C for at least 4 hours. The solid was collected by centrifuge, washed with IPOAc (1.5V), and dried under vacuum at 32 ± 3 °C for at least 24 hours to obtain Durulobacterium calcium salt crystalline form C containing usually 6 - 7% water, less than 1% EtOH, and less than 1% acetone.

[0135]

[0150] Method B:

[0151] DUR-Ca form A was slurried in 26 solvents for 3 days. In most solvents, a new distinct form (referred to as form C) was obtained (Table 19).

[0136]

Table 19

[0137]

[0152] The DUR-Ca Form A was slurried with acetone (5V) and water (3.5 equivalents) at 20 ± 5 °C for 4 to 24 hours. The wet solid was collected by filtration and dried under vacuum to obtain DUR-Ca Form C.

[0138]

[0153] The DUR-Ca crystal Form C was characterized by XRPD (Figure 10 and Table 20), TGA (Figure 11), and DSC (Figure 12). Peaks with relative intensity less than 1% are not reported.

[0139]

Table 20

[0140]

[0154] Preparation and Characterization of Dulrobacterium Calcium Salt Form F

[0155] The inactivation reactor was charged with the following: anhydrous CaCl 2 (7.5 kg, 0.5 equivalent) and ethanol (442 kg, 8V). The reaction mixture was stirred at 20 °C ± 5 °C until completely dissolved and then maintained at this temperature until used in the synthesis.

[0141]

[0156] The second inactivation reactor is continuously charged with the following: DUR-TBA (70 kg, 1 equivalent) and ethanol (276.5 kg, 5V). The reaction mixture is brought to 20°C ± 5°C and stirred at this temperature until dissolved. Next, a calcium chloride solution (previously prepared) is slowly added over a minimum of 1 hour (through a filling container with a dip tube). At the end of the addition, the reactor used for the preparation of the calcium chloride solution is rinsed with ethanol (41.5 kg, 0.75V) and then transferred to the synthesis reactor. The reaction mixture is maintained at 20°C ± 5°C for a minimum of 16 hours. At the end of the contact, the mixture is cooled to 0°C ± 5°C and maintained at this temperature for a minimum of 2 hours. The mixture is filtered and washed with ethanol (110.5 kg, 2V) and acetone (110 kg, 2V) pre-cooled to 0°C ± 5°C. The wet DUR-Ca before the slurry is dried on a filter at a pressure of 1 bar for a minimum of 4 hours. The wet DUR-Ca and 7V (384 kg) of acetone are charged to the reactor, and 2 equivalents of water (4.86 kg) are added over a minimum of 10 minutes at 20°C ± 5°C. Thereafter, the mixture is stirred at 20°C ± 5°C for 2 hours, filtered, and washed with acetone (110 kg, 2V). DUR-Ca is dried on a filter at a pressure of 3 bar for a minimum of 12 hours to obtain crystalline form F, and crystalline form F usually contains a maximum of 20% acetone.

[0142]

[0157] Crystalline form F of DUR-Ca was characterized by XRPD (Figure 13 and Table 21) and TGA and DSC (Figure 14). Peaks with relative intensity less than 1% are not reported.

[0143]

Table 21-1

[0144]

Table 21-2

[0145]

[0158] Different crystalline forms of DUR-Ca contain different levels of solvent. The residual solvent contents are summarized in Table 22.

[0146]

Table 22

[0147]

[0159] The formation of crystalline forms A, B, C, and F is summarized in Figure 15. Synthesis of sodium durulactam (DUR-Na) from other durulactam salts

[0160] Method A - Synthesis of DUR-Na from DUR-TEA

[0161] Purolite® C100E, 1375.0 g, 2500% wt was added to a NaOH solution (2.0 M, 1.0 L) and stirred at 17 °C for 12 hours. The resin was collected, washed with water until the pH reached 7 - 9, and then acidified with glacial acetic acid until the pH reached 5 - 6.

[0148]

[0162] To a solution of DUR-TEA (54.98 g, 145.28 mmol, 1.0 eq) in water (550 mL, 10.0 V) was added the resin prepared above (275 g, 500% wt). The solution was stirred at 17 °C for 1 hour. The resin was filtered and the filtrate was collected as sodium durulactam.

[0149]

[0163] Method B - Synthesis of DUR-Na from DUR-TBA

[0164] Amberlyst15 (wet) - H resin (30.21 g, 57.10 mmol) was slurried with water (100 mL) and poured into a glass column with a diameter of 2 cm (resin bed height: 21.0 cm). The resin was washed with water (150 mL). Sodium chloride (33.65 g, 575.9 mmol) was dissolved in water (540 mL) and the resulting solution was slowly eluted through the resin. The pH was monitored using a pH indicator strip and was shown to change from pH 5 → pH 1 → pH 5. The resin was washed with water (300 mL) and water was allowed to flow until approximately 0.5 cm remained above the resin bed.

[0150]

[0165] A solution of DUR-TBA (352.5 mg, 0.6792 mmol) in water (18 mL) was prepared and carefully applied to the column. The solution was slowly eluted through the column under gravity. The vial containing the DUR-Na solution was rinsed with water (18 mL) and the rinse was also applied to the column. The resin was washed with an additional 35 mL of water. All eluates were collected in a fresh vial. The combined eluates were reapplied to the column and slowly eluted under gravity. The resin was washed with water (35 mL) and the eluates were collected in a fresh vial. The combined eluates were frozen in liquid nitrogen and lyophilized.

[0151]

[0166] The product was isolated as a statically clingy, fluffy white powder (189.9 mg, 93.2% recovery).

[0167] Method C - Synthesis of DUR-Na from DUR-Ca

[0168] DUR-Ca (29.0 kg, 1 equiv.) was added to a pre-cooled (0-5 °C) solution of water (87 kg, 3 V) and stirred until dissolved. Then, a solution of sodium carbonate (4.84 kg of anhydrous Na in 43.6 kg of water) was added. 2 CO 3 ) was added slowly (minimum 1 h) while maintaining the temperature below 5° C. The pH of the reaction mixture was monitored during the base addition to ensure that it did not exceed pH 8.5 throughout the addition. After the addition was complete, the reaction mixture was stirred at 0-5° C. for a minimum of 1 h and then filtered to remove calcium carbonate that had precipitated at the end of the salt exchange. The spent calcium carbonate was rinsed three times (14.5 kg, 0.5 V each wash) with pre-chilled DI water at 0-5° C. The combined filtrates were lyophilized to give DUR-Ca as an amorphous solid.

[0152] Large-scale manufacturing

[0169] A comparison of the purity achieved when forming DUR-Na using the disclosed process versus the process described in WO2013 / 150296 is shown in Table 23 below.

[0153] [Table 23]

[0154]

[0170] Although a number of embodiments have been described, it will be apparent that the basic examples of the present invention can be modified to provide other embodiments that utilize the compounds and methods of the present invention. Accordingly, it is understood that the scope of the present invention is defined by the appended claims, rather than by the specific embodiments presented as examples.

[0155]

[0171] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are hereby expressly incorporated by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein shall have the meanings commonly known to those of ordinary skill in the art.

Claims

1. Structural formula I: 【Chemical 1】 (wherein n is 1 or 2, X is a positively charged amine or a Ca, Mg, Zn, K, Na, Li, Cs, Ba, Rb, Sr, Fe, Co, Ni, Cu, Zn, Ag, or Au cation) A salt of a compound having the same.

2. The salt of the compound according to claim 1, wherein X is a positively charged amine or a Ca cation.

3. The salt of the compound according to claim 1 or 2, wherein X is a positively charged amine.

4. The salt of the compound according to any one of claims 1 to 3, wherein X is a protonated tertiary amine or a quaternary ammonium.

5. The salt of the compound according to any one of claims 1 to 4, wherein X is trimethylammonium, triethylammonium, tributylammonium, triisopropylammonium, or N,N - diisopropylethylammonium.

6. The salt of the compound according to any one of claims 1 to 4, wherein X is triethylammonium.

7. Structural formula: 【Chemical Formula 2】 The salt of the compound according to any one of claims 1 to 6, which is of the above formula.

8. The salt of the compound according to any one of claims 1 to 7, which is crystalline.

9. The salt of the compound according to claim 7 or 8, which is in crystalline form A.

10. The salt of the compound according to claim 9, wherein crystalline form A is characterized by at least three X - ray powder diffraction peaks at 2Θ angles selected from 9.5°, 10.7°, 12.7°, 13.5°, 17.3°, 22.6°, and 24.4°.

11. The salt of the compound according to claim 9 or 10, wherein crystalline form A is characterized by at least four X - ray powder diffraction peaks at 2Θ angles selected from 9.5°, 10.7°, 12.7°, 13.5°, 17.3°, 22.6°, and 24.4°.

12. The salt of the compound according to any one of claims 9 to 11, wherein crystalline form A is characterized by at least five X - ray powder diffraction peaks at 2Θ angles selected from 9.5°, 10.7°, 12.7°, 13.5°, 17.3°, 22.6°, and 24.4°.

13. The salt of the compound according to any one of claims 9 to 12, wherein crystalline form A is characterized by at least six X - ray powder diffraction peaks at 2Θ angles selected from 9.5°, 10.7°, 12.7°, 13.5°, 17.3°, 22.6°, and 24.4°.

14. The salt of the compound according to any one of claims 9 to 13, wherein the crystalline form A is characterized by X-ray powder diffraction peaks at 2θ angles of 9.5°, 10.7°, 12.7°, 13.5°, 17.3°, 22.6°, and 24.4°.

15. The crystalline form A according to any one of claims 9 to 14, wherein at least 70% by weight is in single crystal form, at least 80% by weight is in single crystal form, at least 90% by weight is in single crystal form, at least 95% by weight is in single crystal form, or at least 99% by weight is in single crystal form.

16. The salt of the compound according to claim 9, wherein the crystalline form A is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

3.

17. The salt of the compound according to any one of claims 1 to 4, wherein X is tetrabutylammonium, tetraethylammonium, tetramethylammonium, or tetrapropylammonium.

18. The salt of the compound according to any one of claims 1 to 4 and 17, wherein X is tetrabutylammonium.

19. Structural formula: 【Chemical Formula 3】 The salt of the compound according to any one of claims 1 to 4, 17, and 18, which is of the following formula:

20. The salt of the compound according to claim 18 or 19, which is crystalline.

21. The salt of the compound according to any one of claims 18 to 20, which is in crystalline form A.

22. The salt of the compound according to claim 21, wherein the crystalline form A is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 7.3°, 8.5°, 8.7°, 10.3°, 12.7°, 19.5°, and 21.4°.

23. The salt of the compound according to claim 21 or 22, wherein the crystalline form A is characterized by at least four X-ray powder diffraction peaks at 2θ angles selected from 7.3°, 8.5°, 8.7°, 10.3°, 12.7°, 19.5°, and 21.4°.

24. The salt of the compound according to any one of claims 21 to 23, wherein the crystalline form A is characterized by at least five X-ray powder diffraction peaks at 2θ angles selected from 7.3°, 8.5°, 8.7°, 10.3°, 12.7°, 19.5°, and 21.4°.

25. The salt of the compound according to any one of claims 21 to 24, wherein crystalline form A is characterized by at least six X-ray powder diffraction peaks at 2θ angles selected from 7.3°, 8.5°, 8.7°, 10.3°, 12.7°, 19.5° and 21.4°.

26. The salt of the compound according to any one of claims 21 to 25, wherein crystalline form A is characterized by X-ray powder diffraction peaks at 2θ angles of 7.3°, 8.5°, 8.7°, 10.3°, 12.7°, 19.5° and 21.4°.

27. The salt of the compound according to any one of claims 21 to 26, wherein crystalline form A is at least 70% by weight in single crystal form, at least 80% by weight in single crystal form, at least 90% by weight in single crystal form, at least 95% by weight in single crystal form, or at least 99% by weight in single crystal form.

28. The salt of the compound according to claim 21, wherein crystalline form A is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

1.

29. The salt of the compound according to claim 1 or 2, wherein the cation is Ca.

30. Structural formula: [Chemical 4] The salt of the compound according to any one of claims 1, 2 and 29, which is of the following formula.

31. The salt of the compound according to claim 29 or 30, which is crystalline.

32. The salt of the compound according to any one of claims 29 to 31, which is in crystalline form A, B, C or F.

33. The salt of the compound according to claim 32, wherein crystalline form B is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 9.6°, 12.5°, 12.7°, 14.1°, 16.5°, 16.6, 22.5°, and 24.6°.

34. The salt of the compound according to claim 32 or 33, wherein crystalline form B is characterized by at least four X-ray powder diffraction peaks at 2θ angles selected from 9.6°, 12.5°, 12.7°, 14.1°, 16.5°, 16.6, 22.5°, and 24.6°.

35. The salt of the compound according to any one of claims 32, 33 and 34, wherein crystalline form B is characterized by at least five X-ray powder diffraction peaks at 2θ angles selected from 9.6°, 12.5°, 12.7°, 14.1°, 16.5°, 16.6, 22.5°, and 24.6°.

36. The salt of the compound according to any one of claims 32 and 33 to 35, wherein crystalline form B is characterized by at least six X-ray powder diffraction peaks at 2Θ angles selected from 9.6°, 12.5°, 12.7°, 14.1°, 16.5°, 16.6, 22.5°, and 24.6°.

37. The salt of the compound according to any one of claims 32 and 33 to 36, wherein crystalline form B is characterized by at least seven X-ray powder diffraction peaks at 2Θ angles selected from 9.6°, 12.5°, 12.7°, 14.1°, 16.5°, 16.6, 22.5°, and 24.6°.

38. The salt of the compound according to any one of claims 32 and 33 to 37, wherein crystalline form B is characterized by X-ray powder diffraction peaks at 2Θ angles of 9.6°, 12.5°, 12.7°, 14.1°, 16.5°, 16.6, 22.5°, and 24.6°.

39. The salt of the compound according to any one of claims 33 to 38, wherein crystalline form B is at least 70% by weight in single crystal form, at least 80% by weight in single crystal form, at least 90% by weight in single crystal form, at least 95% by weight in single crystal form, or at least 99% by weight in single crystal form.

40. The salt of the compound according to claim 32, wherein crystalline form B is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

5.

41. The salt of the compound according to claim 32, wherein crystalline form A is characterized by at least three X-ray powder diffraction peaks at 2Θ angles selected from 7.8°, 9.0°, 11.9°, 13.4°, 16.2°, 19.5°, 20.5°, and 25.0°.

42. The salt of the compound according to claim 32 or 41, wherein crystalline form A is characterized by at least four X-ray powder diffraction peaks at 2Θ angles selected from 7.8°, 9.0°, 11.9°, 13.4°, 16.2°, 19.5°, 20.5°, and 25.0°.

43. The salt of the compound according to any one of claims 32, 41, and 42, wherein crystalline form A is characterized by at least five X-ray powder diffraction peaks at 2Θ angles selected from 7.8°, 9.0°, 11.9°, 13.4°, 16.2°, 19.5°, 20.5°, and 25.0°.

44. The salt of the compound according to any one of claims 32 and 41 to 43, wherein the crystalline form A is characterized by at least six X-ray powder diffraction peaks at 2Θ angles selected from 7.8°, 9.0°, 11.9°, 13.4°, 16.2°, 19.5°, 20.5°, and 25.0°.

45. The salt of the compound according to any one of claims 32 and 41 to 44, wherein the crystalline form A is characterized by at least seven X-ray powder diffraction peaks at 2Θ angles selected from 7.8°, 9.0°, 11.9°, 13.4°, 16.2°, 19.5°, 20.5°, and 25.0°.

46. The salt of the compound according to any one of claims 32 and 41 to 45, wherein the crystalline form A is characterized by X-ray powder diffraction peaks at 2Θ angles of 7.8°, 9.0°, 11.9°, 13.4°, 16.2°, 19.5°, 20.5°, and 25.0°.

47. The salt of the compound according to any one of claims 41 to 46, wherein the crystalline form A is at least 70% by weight in single crystal form, at least 80% by weight in single crystal form, at least 90% by weight in single crystal form, at least 95% by weight in single crystal form, or at least 99% by weight in single crystal form.

48. The salt of the compound according to claim 32, wherein the crystalline form A is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

7.

49. The salt of the compound according to claim 32, wherein the crystalline form C is characterized by at least three X-ray powder diffraction peaks at 2Θ angles selected from 7.0°, 12.2°, 16.1°, 16.9°, 19.7°, 20.3°, and 26.9°.

50. The salt of the compound according to claim 32 or 49, wherein the crystalline form C is characterized by at least four X-ray powder diffraction peaks at 2Θ angles selected from 7.0°, 12.2°, 16.1°, 16.9°, 19.7°, 20.3°, and 26.9°.

51. The salt of the compound according to any one of claims 32, 49, and 50, wherein the crystalline form C is characterized by at least five X-ray powder diffraction peaks at 2Θ angles selected from 7.0°, 12.2°, 16.1°, 16.9°, 19.7°, 20.3°, and 26.9°.

52. The salt of the compound according to any one of claims 32 and 49 to 51, wherein crystalline form C is characterized by at least six X-ray powder diffraction peaks at 2Θ angles selected from 7.0°, 12.2°, 16.1°, 16.9°, 19.7°, 20.3°, and 26.9°.

53. The salt of the compound according to any one of claims 32 and 49 to 52, wherein crystalline form C is characterized by at least seven X-ray powder diffraction peaks at 2Θ angles selected from 7.0°, 12.2°, 16.1°, 16.9°, 19.7°, 20.3°, and 26.9°.

54. The salt of the compound according to any one of claims 32 and 49 to 53, wherein crystalline form C is characterized by X-ray powder diffraction peaks at 2Θ angles of 7.0°, 12.2°, 16.1°, 16.9°, 19.7°, 20.3°, and 26.9°.

55. The salt of the compound according to any one of claims 32 and 49 to 54, wherein crystalline form C is at least 70% by weight in single crystal form, at least 80% by weight in single crystal form, at least 90% by weight in single crystal form, at least 95% by weight in single crystal form, or at least 99% by weight in single crystal form.

56. The salt of the compound according to claim 32, wherein crystalline form C is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

10.

57. The salt of the compound according to claim 32, wherein crystalline form F is characterized by at least three X-ray powder diffraction peaks at 2Θ angles selected from 9.5°, 11.3°, 12.0°, 14.0°, 17.0°, 19.0°, 22.3°, and 24.2°.

58. The salt of the compound according to claims 32 and 57, wherein crystalline form F is characterized by at least four X-ray powder diffraction peaks at 2Θ angles selected from 9.5°, 11.3°, 12.0°, 14.0°, 17.0°, 19.0°, 22.3°, and 24.2°.

59. The salt of the compound according to any one of claims 32, 57, and 58, wherein crystalline form F is characterized by at least five X-ray powder diffraction peaks at 2Θ angles selected from 9.5°, 11.3°, 12.0°, 14.0°, 17.0°, 19.0°, 22.3°, and 24.2°.

60. The salt of the compound according to any one of claims 32 and 57 to 59, wherein the crystalline form F is characterized by at least six X-ray powder diffraction peaks at 2θ angles selected from 9.5°, 11.3°, 12.0°, 14.0°, 17.0°, 19.0°, 22.3°, and 24.2°.

61. The salt of the compound according to any one of claims 32 and 57 to 60, wherein the crystalline form F is characterized by at least seven X-ray powder diffraction peaks at 2θ angles selected from 9.5°, 11.3°, 12.0°, 14.0°, 17.0°, 19.0°, 22.3°, and 24.2°.

62. The salt of the compound according to any one of claims 32 and 57 to 61, wherein the crystalline form F is characterized by X-ray powder diffraction peaks at 2θ angles of 9.5°, 11.3°, 12.0°, 14.0°, 17.0°, 19.0°, 22.3°, and 24.2°.

63. The salt of the compound according to any one of claims 32 and 57 to 62, wherein the crystalline form F is at least 70% by weight in single crystal form, at least 80% by weight in single crystal form, at least 90% by weight in single crystal form, at least 95% by weight in single crystal form, or at least 99% by weight in single crystal form.

64. The salt of the compound according to claim 32, wherein the crystalline form F is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

13.

65. A method for preparing a calcium salt of a compound having the formula: 【Chemical Formula 5】 comprising the step of reacting a tetrabutylammonium salt having the formula with calcium chloride to form a calcium salt. ​ The method comprising the step.

66. The method according to claim 65, wherein the tetrabutylammonium salt is reacted with calcium chloride in ethanol.

67. The method according to claims 65 and 66, wherein the calcium salt is in crystalline form A, B, C or F.

68. A method for preparing a triethylammonium salt of a compound having the formula: 【Chemical Formula 7】 comprising the step of reacting a hydroxyurea compound having the structural formula with a sulfur trioxide pyridine complex and triethylamine to form a triethylammonium salt. [Chemical Formula 8] The method comprising the step.

69. The method according to claim 68, wherein the hydroxyurea compound is reacted with a sulfur trioxide pyridine complex and trimethylamine in acetonitrile.

70. The method according to claim 68 or 69, further comprising the step of precipitating the triethylammonium salt from the solution.

71. The method according to claim 70, wherein the triethylammonium salt is precipitated from acetone.

72. The method according to any one of claims 68 to 71, wherein the triethylammonium salt is in crystalline form A.

73. Formula: 【Chemical Formula 9】 A method for preparing a tetrabutylammonium salt of a compound having Formula: 【Chemical Formula 10】 reacting a triethylammonium salt of a compound having with tetrabutylammonium hydrogen sulfate and sodium dihydrogen phosphate to form a tetrabutylammonium salt comprising the method.

74. The method according to claim 73, further comprising the step of precipitating the tetrabutylammonium salt from acetone.

75. The method according to claim 73 or 74, wherein the tetrabutylammonium salt is in crystalline form A.

76. Formula: 【Chemical 11】 A method for preparing a sodium salt of a compound having i) a triethylammonium salt of a compound having 【Chemical 12】 or ii) a tetrabutylammonium salt of a compound having reacting with an ion exchange resin containing sodium to form a sodium salt 【Chemical 13】 comprising the method.

77. A method for preparing a sodium salt of a compound having Formula: reacting a calcium salt of a compound having with sodium carbonate to form a sodium salt 【Chemical Formula 14】 comprising the method.

78. 【Chemical Formula 15】 Formula: A method for preparing a sodium salt of a compound having

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