Method for manufacturing oxo-substituted compound

Abstract

The present disclosure provides a salt (including a crystal) of an oxo-substituted compound useful as a pharmaceutical product, a pharmaceutical composition containing the same, and a usage thereof in a treatment, and a method for manufacturing a salt of the oxo-substituted compound and a crystal thereof, a manufacturing intermediate thereof, and a method for manufacturing the manufacturing intermediate.

Description

Method for producing oxo-substituted compounds

[0001] This disclosure relates to salts (including crystals) of oxosubstituted compounds useful as pharmaceuticals, pharmaceutical compositions containing them, and their use in therapy, as well as methods for producing said oxosubstituted compound salts and crystals, intermediates for the production thereof, and methods for producing said intermediates.

[0002] A method for producing oxo-substituted compounds having β-lactamase inhibitory activity, and related substances, is known, for example, the method described in Patent Document 1. Furthermore, the usage, dosage, and applications of oxo-substituted compounds are reported in Patent Document 2.

[0003] International Publication No. 2019 / 208797, International Publication No. 2024 / 128238

[0004] This disclosure provides novel salts of a compound having excellent β-lactamase inhibitory activity, its crystals (crystalline polymorphs), and methods for producing the same, and provides useful prophylactic or therapeutic agents for bacterial infections, either in combination with β-lactam drugs (including administration as a combination or separately) or as a monotherapy. Specifically, the present invention provides a preventive or therapeutic agent useful for the treatment of diseases such as sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infections of chronic respiratory diseases, pharyngitis / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infections, lymphangitis / lymphadenitis, secondary infections of trauma / burns and surgical wounds, urinary tract infections, genital infections, eye infections, dental infections, complicated urinary tract infections, complicated intra-abdominal infections, hospital-acquired pneumonia, and ventilator-associated pneumonia, either in combination with or as a monotherapy with β-lactam antibiotics.

[0005] More specifically, the present inventors, through diligent research, have found that the oxosubstituted compound 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid can be obtained as a crystalline phosphate, malonate, tartrate, phosphate tartrate (a mixed salt of two different acids consisting of phosphoric acid and tartaric acid), or hydrochloride phosphate (a mixed salt of two different acids consisting of hydrochloric acid and phosphoric acid). Furthermore, they have found that these salts can be produced simply, in high yield and inexpensively, with few steps, at a level that allows for large-scale synthesis for pharmaceutical industries. Moreover, they have found that these salts can be obtained as stable crystals (crystalline polymorphs) of forms I to VIII.

[0006] In one embodiment of the industrial manufacturing method of the present disclosure, specifically, a manufacturing intermediate (2) is obtained by protecting two hydroxyl groups and a carboxyl group of a dihydroxybenzoic acid derivative (1) (Bocation and t-Bu esterification, respectively) (Step 1). A manufacturing intermediate (3) is obtained by selective deprotection (de-Bocation) of the 6-position hydroxyl group of intermediate (2) (Step 2), and subsequently, a manufacturing intermediate (4) is obtained by a Mitsunobu reaction with NH-protected azetidine-3-ol (K) (Step 3). A manufacturing intermediate (5) is obtained by a vinylation reaction of intermediate (4) (Step 4), and subsequently, a manufacturing intermediate (6) is obtained by a hydroboration reaction (Step 5). The azetidine group of intermediate (6) is deprotected (protecting group PG １ By removing the protective group (PG), and converting to the hydrochloride salt, a manufacturing intermediate (7) was obtained (Step 6), and subsequently, by a condensation reaction with an amino group-protected amino acid derivative (D) (described in manufacturing method 4 below), a manufacturing intermediate (8) was obtained (Step 7). Deprotection of the amino group of intermediate (8) (protecting group PG ５By removing (Step 8), a manufacturing intermediate (9) was obtained, and subsequently, a manufacturing intermediate (10) was obtained by salt formation with a tartaric acid derivative (L) (Step 9). Finally, by treating the intermediate (10) with phosphoric acid, it was found that an optically active oxosubstituted compound (11c) of form III, one of the crystalline forms (crystalline polymorphs) of phosphate, could be obtained in a small number of steps, easily, in high yield and inexpensively, at a level that would allow for large-scale synthesis for pharmaceutical industries (Manufacturing Method 1).

[0007] In another embodiment of the industrial manufacturing method of this disclosure, it has been found that optically active oxosubstituted compounds (11c) can be obtained simply, in high yield and inexpensively, in even fewer steps than in manufacturing method 1, by treating the manufacturing intermediate (8) obtained by the steps up to Step 7 of manufacturing method 1 with phosphoric acid (manufacturing method 2).

[0008] The inventors have also discovered crystalline forms of optically active oxosubstituted compounds different from form III, and in yet another embodiment of the industrial manufacturing method of this disclosure, specifically, the oxosubstituted compound of form III (11c) obtained by manufacturing method 1 or manufacturing method 2 is treated with phosphoric acid in water or an inert solvent containing water (crystallization method), or treated in an inert solvent containing water (slurry method) to obtain the compound of form I (11a) or the compound of form II (11b) or a mixture thereof (Step 12). The compound of form II (11b) is finally converted to the compound of form I (11a) by conditioning (Step 13). By the above manufacturing method, as described later, it has also been found that an optically active oxosubstituted compound (11a) of a specific crystalline form I of a phosphate, which is particularly stable and useful, can be obtained selectively, simply, in high yield and inexpensively, at a level that allows for large-scale synthesis for pharmaceutical industries (manufacturing method 3).

[0009] In yet another embodiment of the industrial manufacturing method of the present disclosure, specifically, a manufacturing intermediate (B) is obtained by hydantoinization of imidazole-4-carboxyaldehyde (A) (Step A). ​​A manufacturing intermediate (C') is obtained by ring-opening reaction of intermediate (B) (Step B), and subsequently, a manufacturing intermediate (C) is obtained by salt formation with L-tartaric acid (Step C). Finally, intermediate (C) is liberated and the amino group and imidazolyl group are protected (protecting group PG ４ and PG ５ By introducing [the necessary technology / method], we also found that optically active amino acid derivatives (D) can be obtained in a simple, high-yield, and inexpensive manner with fewer steps, at a level that allows for large-scale synthesis for pharmaceutical industrial use (Manufacturing Method 4).

[0010] Manufacturing method 1

[0011] Manufacturing method 2

[0012] Manufacturing method 3

[0013] Manufacturing method 4

[0014] In yet another embodiment of the industrial manufacturing method of this disclosure, it has also been found that stable crystalline forms IV to VIII can be obtained from optically active oxosubstituted compounds under specific crystallization conditions, etc., as crystalline forms of salts of specific acids described later (malonate, D-tartrate, D-tartrate phosphate, and phosphate hydrochloride).

[0015] Based on the above, this disclosure is now complete. Specifically, this disclosure is as follows:

[0016] [Item 1] A pharmaceutically acceptable salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid, wherein the pharmaceutically acceptable salt is selected from the group consisting of phosphate, malonate, D-tartrate, D-tartrate phosphate, and phosphate hydrochloride.

[0017] [Clause 2] The salt according to Claim 1, wherein the pharmaceutically acceptable salt is a phosphate. [Clause 3] The salt according to Claim 2, wherein the phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 9.8 ± 0.2° and 12.5 ± 0.2°. [Clause 4] The salt according to Claim 2, wherein the phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 9.8±0.2°, 12.5±0.2°, 12.6±0.2°, 14.2±0.2°, 14.6±0.2°, 16.0±0.2°, 20.0±0.2°, 20.2±0.2°, 20.4±0.2°, 21.2±0.2°, 22.6±0.2°, 23.5±0.2°, 24.1±0.2°, and 25.1±0.2°. [Clause 5] The salt according to Claim 3 or Claim 4, wherein the crystalline phosphate is morphology I. [Item 6] The salt according to any one of items 3 to 5, wherein the phosphate is crystalline and the crystal exhibits a differential scanning calorimetry curve having an endothermic peak around 221°C.

[0018] [Clause 7] The salt according to Claim 2, wherein the phosphate is crystalline and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 5.3±0.2° and 10.6±0.2°. [Clause 8] The salt according to Claim 2, wherein the phosphate is crystalline and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 5.3±0.2°, 10.6±0.2°, 13.5±0.2°, 15.6±0.2°, 18.1±0.2°, 18.6±0.2°, 20.1±0.2°, 21.6±0.2°, 24.1±0.2°, 25.8±0.2°, and 29.4±0.2°. [Clause 9] The salt according to Claim 7 or Claim 8, wherein the phosphate crystal is morphology II.

[0019] [Clause 10] The salt according to Claim 2, wherein the phosphate is crystalline and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 9.9±0.2° and 16.5±0.2°. [Clause 11] The salt according to Claim 2, wherein the phosphate is crystalline and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 9.9±0.2°, 15.4±0.2°, 16.5±0.2°, 20.2±0.2°, 20.6±0.2°, 21.2±0.2°, 22.0±0.2°, 22.9±0.2°, 23.8±0.2°, 24.3±0.2°, and 24.6±0.2°. [Clause 12] The salt according to Claim 10 or Claim 11, wherein the phosphate crystal is of form III.

[0020] [Clause 13] The salt according to Clause 1, wherein the pharmaceutically acceptable salt is a malonate.

[0021] [Clause 14] The salt according to Claim 13, wherein the malonate is crystalline and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 11.7±0.2° and 12.3±0.2°. [Clause 15] The salt according to Claim 13, wherein the malonate is crystalline and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 6.3±0.2°, 11.7±0.2°, 12.3±0.2°, 16.6±0.2°, 20.5±0.2°, 21.3±0.2°, 21.9±0.2°, 22.2±0.2°, 22.8±0.2°, 23.4±0.2°, 25.1±0.2°, and 27.6±0.2°. [Clause 16] The salt according to Claim 14 or Claim 15, wherein the malonate crystals are of form IV.

[0022] [Clause 17] The salt according to Claim 13, wherein the malonate is crystalline and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 10.8±0.2° and 21.7±0.2°. [Clause 18] The salt according to Claim 13, wherein the malonate is crystalline and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 8.9±0.2°, 10.8±0.2°, 14.7±0.2°, 15.3±0.2°, 17.0±0.2°, 18.2±0.2°, 21.7±0.2°, 23.0±0.2°, 24.2±0.2°, 25.4±0.2°, 28.4±0.2°, and 28.7±0.2°. [Clause 19] The salt according to clause 17 or 18, wherein the malonate crystals are of form V.

[0023] [Clause 20] The salt according to Claim 1, wherein the pharmaceutically acceptable salt is D-tartrate. [Clause 21] The salt according to Claim 20, wherein the D-tartrate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 12.7 ± 0.2° and 16.5 ± 0.2°. [Clause 22] The salt according to Claim 20, wherein the D-tartrate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 10.4±0.2°, 11.8±0.2°, 12.2±0.2°, 12.7±0.2°, 14.6±0.2°, 15.6±0.2°, 16.5±0.2°, 21.1±0.2°, 21.8±0.2°, 22.9±0.2°, 23.5±0.2°, 24.7±0.2°, and 26.6±0.2°. [Clause 23] The salt according to Claim 21 or Claim 22, wherein the crystal of the D-tartrate is morphological VI.

[0024] [Clause 24] The salt according to Claim 1, wherein the pharmaceutically acceptable salt is D-tartrate phosphate. [Clause 25] The salt according to Claim 24, wherein the D-tartrate phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 9.6 ± 0.2° and 23.6 ± 0.2°. [Clause 26] The salt according to Claim 24, wherein the D-tartrate phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 9.6±0.2°, 13.3±0.2°, 17.1±0.2°, 19.8±0.2°, 21.4±0.2°, 22.0±0.2°, 23.6±0.2°, 25.2±0.2°, 26.4±0.2°, 27.4±0.2°, and 28.4±0.2°. [Clause 27] The salt according to Claim 25 or Claim 26, wherein the crystal of the D-tartrate phosphate is morphology VII.

[0025] [Clause 28] The salt according to Claim 1, wherein the pharmaceutically acceptable salt is hydrochloride phosphate. [Clause 29] The salt according to Claim 28, wherein the hydrochloride phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 10.4 ± 0.2° and 25.9 ± 0.2°. [Clause 30] The salt according to Claim 28, wherein the hydrochloric acid phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 10.4±0.2°, 14.2±0.2°, 15.5±0.2°, 18.2±0.2°, 19.0±0.2°, 20.7±0.2°, 21.8±0.2°, 22.7±0.2°, 25.2±0.2°, 25.9±0.2°, 27.4±0.2°, 28.3±0.2°, 31.1±0.2°, and 31.6±0.2°. [Clause 31] The salt according to Claim 29 or Claim 30, wherein the crystalline hydrochloric acid phosphate is morphological VIII.

[0026] [Item 101] A pharmaceutical product containing a salt as described in any one of items 1 to 31 as an active ingredient. [Item 102] The pharmaceutical product according to item 101, which is a therapeutic or prophylactic agent for bacterial infections. [Item 103] The pharmaceutical product according to item 102, wherein the bacterial infection is a bacterial infection involving bacteria that may possess β-lactamase. [Clause 104] The medicine described in paragraph 102 or 103, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory disease, pharyngitis / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphangitis / lymphadenitis, secondary infection of wounds, burns and surgical wounds, urinary tract infection, genital infection, eye infection, dental infection, complicated urinary tract infection, complicated intra-abdominal infection, hospital-acquired pneumonia or ventilator-associated pneumonia.

[0027] [Item 105] A β-lactamase inhibitor containing a salt described in any one of items 1 to 31 as an active ingredient.

[0028] [Claim 106] A pharmaceutical composition comprising a salt according to any one of claims 1 to 31 and a pharmaceutically acceptable carrier. [Claim 107] The pharmaceutical composition according to claim 106, further comprising an additional agent. [Claim 108] The pharmaceutical composition according to claim 107, wherein the additional agent is selected from the group consisting of antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, and antiallergic agents. [Claim 109] The pharmaceutical composition according to claim 107 or claim 108, wherein the additional agent is a β-lactam agent.[Item 110] β-lactam drugs include amoxicillin, ampicillin (pivanpicillin, hetacillin, bacampicillin, metampicillin, tarampicillin), epicillin, carbenicillin (kalindacillin), ticarcillin, temocillin, azurocillin, piperacillin, mezlocillin, mesilinum (pibmesilinum), sulbenicillin, benzylpecillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin (V), propicillin, Benzatin, phenoxymethylpenicillin, pheneticillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razpenem, cefazolin, cefacetril, cefadroxyl, cephalexin, cephaloglysin, cephalonium, cephaloridine, cephalothin, cefapillin, cefatoridine, cefazedone, cefazalflu, cefradiin, cefuroxa Zin, ceftezol, cefaclor, cephamandol, cefminox, cefonisid, cefolanide, cefotiam, cefprodil, cefbuperazone, cefuroxime, cefzonam, cefoxitin, cefotetan, cefmetazole, loracalbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaroxime, cefdinir, cefditoren, cefetameth, cefmenoxime, cefozidime, cefoperazone, cefotaxime, cefpimisole, cefpyramide, cefpodoxime, cefsurodin, cefte A pharmaceutical composition according to item 109, selected from the group consisting of lamb, ceftibutene, cefthiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftoviprole, cephthaloline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefobesin, aztreonam, tigenonam, carmonam, RWJ-442831, RWJ-333441, and RWJ-333442.[Claim 111] The pharmaceutical composition according to claim 109, wherein the β-lactam drug is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem. [Claim 112] The pharmaceutical composition according to claim 109, wherein the β-lactam drug is selected from the group consisting of aztreonam, tigenonam, BAL30072, SYN2416, and carmonam.

[0029] [Claim 113] The pharmaceutical composition according to claim 106, comprising an additional agent. [Claim 114] The pharmaceutical composition according to claim 113, wherein the additional agent is selected from the group consisting of antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, and antiallergic agents. [Claim 115] The pharmaceutical composition according to claim 113 or claim 114, wherein the additional agent is a β-lactam agent.[Item 116] Beta-lactam drugs include amoxicillin, ampicillin (pivanpicillin, hetacillin, bacampicillin, metampicillin, tarampicillin), epicillin, carbenicillin (kalindacillin), ticarcillin, temocillin, azurocillin, piperacillin, mezlocillin, mesilinum (pibmesilinum), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin (V), and propicillin. Benzathin, phenoxymethylpenicillin, pheneticillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razpenem, cefazolin, cefacetril, cefadroxyl, cephalexin, cephaloglysin, cephalonium, cephaloridine, cephalothin, cefapillin, cefatoridine, cefazedone, cefazalflu, cefradiin, cefflox Sazin, ceftezol, cefaclor, cephamandol, cefminox, cefonisid, cefolanide, cefotiam, cefprodil, cefbuperazone, cefuroxime, cefzonam, cefoxitin, cefotetan, cefmetazole, loracalbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaroxime, cefdinir, cefditoren, cefetameth, cefmenoxime, cefozidime, cefoperazone, cefotaxime, cefpimisole, cefpyramide, cefpodoxime, cefsurodin, cefte A pharmaceutical composition according to claim 115, selected from the group consisting of lamb, ceftibutene, cefthiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftoviprole, cephthaloline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefobesin, aztreonam, tigenonam, carmonam, RWJ-442831, RWJ-333441, and RWJ-333442.[Claim 117] The pharmaceutical composition according to claim 115, wherein the β-lactam drug is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem. [Claim 118] The pharmaceutical composition according to claim 115, wherein the β-lactam drug is selected from the group consisting of aztreonam, tigenonam, BAL30072, SYN2416, and carmonam.

[0030] [Section 119] A salt according to any one of sections 1 to 31 for the treatment of a bacterial infection. [Section 120] A salt according to section 119, wherein the bacterial infection is a bacterial infection involving bacteria that may possess β-lactamase. [Section 121] A salt according to section 119 or 120, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory disease, pharyngitis / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphangitis / lymphadenitis, secondary infection of wounds, burns and surgical wounds, urinary tract infection, genital infection, eye infection, odontogenic infection, complicated urinary tract infection, complicated intra-abdominal infection, hospital-acquired pneumonia or ventilator-associated pneumonia.

[0031] [Item 122] A pharmaceutical product comprising a salt described in any one of items 1 to 31, and at least one drug selected from the group consisting of agents for the treatment of sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory diseases, pharyngitis / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphangitis / lymphadenitis, secondary infection of wounds, burns and surgical wounds, urinary tract infection, genital infection, eye infection, dental infection, complicated urinary tract infection, complicated intra-abdominal infection, hospital-acquired pneumonia and ventilator-associated pneumonia.

[0032] [Item 123] A pharmaceutical composition comprising a β-lactam drug, characterized in that the pharmaceutical composition is administered together with a salt described in any one of items 1 to 31.

[0033] [Clause 124] A method for treating a bacterial infection, characterized by administering a therapeutically effective amount of the salt described in any one of Clauses 1 to 31 to a patient in need of treatment. [Clause 125] The method according to Clause 124, wherein the bacterial infection is a bacterial infection involving bacteria that may possess β-lactamase. [Clause 126] The method according to Claim 124 or Claim 125, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory disease, pharyngitis / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphangitis / lymphadenitis, secondary infection of wounds, burns and surgical wounds, urinary tract infection, genital infection, eye infection, dental infection, complicated urinary tract infection, complicated intra-abdominal infection, hospital-acquired pneumonia or ventilator-associated pneumonia. [Clause 127] The method according to any one of Claims 124 to 126, characterized by being administered with an additional agent. [Clause 128] The method according to Claim 127, wherein the additional agent is selected from the group consisting of antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, and antiallergic agents. [Clause 129] The method according to Claim 127 or Claim 128, wherein the additional agent is a β-lactam drug.[Item 130] Beta-lactam drugs include amoxicillin, ampicillin (pivanpicillin, hetacillin, bacampicillin, metampicillin, tarampicillin), epicillin, carbenicillin (kalindacillin), ticarcillin, temocillin, azurocillin, piperacillin, mezlocillin, mesilinum (pibmesilinum), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin (V), and propicillin. Benzatin, phenoxymethylpenicillin, pheneticillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razpenem, cefazolin, cefacetril, cefadroxyl, cephalexin, cephaloglysin, cephalonium, cephaloridine, cephalothin, cefapillin, cefatoridine, cefazedone, cefazalflu, cefradiin, cefuro Xazazine, ceftezol, cefaclor, cephamandol, cefminox, cefonisid, cefolanide, cefotiam, cefprodil, cefbuperazone, cefuroxime, cefzonam, cefoxitin, cefotetan, cefmetazole, loracalbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaroxime, cefdinir, cefditoren, cefetameth, cefmenoxime, cefozidime, cefoperazone, cefotaxime, cefpimisole, cefpyramide, cefpodoxime, cefsulodine, cef The method according to item 129, selected from the group consisting of fteram, ceftibutene, cefthiolen, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirom, cefquinome, ceftoviprole, cephthaloline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefobesin, aztreonam, tigenonam, carmonam, RWJ-442831, RWJ-333441, and RWJ-333442.[Item 131] The method according to Item 129, wherein the β-lactam agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem. [Item 132] The method according to Item 129, wherein the β-lactam agent is selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN2416, and carumonam.

[0034] [Item 133] Use of the salt according to any one of Items 1 to 31 for producing a β-lactamase inhibitor. [Item 134] Use of the salt according to any one of Items 1 to 31 for producing a therapeutic agent for bacterial infections. [Item 135] The use according to Item 134, wherein the bacterial infection is a bacterial infection involving bacteria that may have β-lactamase. [Item 136] The use according to Item 134 or Item 135, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory lesions, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphangitis / lymphadenitis, secondary infection of trauma / burn and surgical wounds, urinary tract infection, genital infection, eye infection, dental infection, complicated urinary tract infection, complicated intra-abdominal infection, hospital-acquired pneumonia or ventilator-associated pneumonia. [Item 201] A method for producing a compound represented by the following formula (11a) (also referred to as an oxo-substituted compound (11a) herein) including the following Step 7: Step 7 A compound represented by the formula (7) [wherein PG ２ and PG ３ are each independently a protecting group for boronic acid.] is subjected to a condensation reaction with an amino acid derivative represented by the formula (D) or a salt thereof [wherein PG ４ and PG ５ are each independently a protecting group for an amino group.] to produce a compound represented by the formula (8) [wherein PG ２ , PG ３ , PG ４ and PG ５ are as defined above.]​​

[0035] [Clause 202] The method of production according to Clause 201, wherein the reaction in Step 7 is carried out under a solvent selected from an amide solvent, an aromatic hydrocarbon solvent, a nitrile solvent, an ether solvent, and an ester solvent. [Clause 203] The method of production according to Clause 201 or Clause 202, wherein the reaction in Step 7 is carried out in a temperature range of about -5°C to about 40°C. [Clause 204] The method for producing a product according to any one of claims 201 to 203, wherein the reaction in Step 7 is carried out in the presence of a coupling agent selected from O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), (hydroxyimino)cyanoethyl acetate (Oxima), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), N,N-carbonyldimidazole (CDI), 1H-benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), and propylphosphonic anhydride (T3P).

[0036] [Clause 205] The manufacturing method according to any one of Clauses 201 to 204, further comprising Step 8 below: Step 8 Formula (8) Compound represented by the formula [wherein PG ２ PG ３ PG ４ and PG ５ This is equivalent to the above. By subjecting [ to the deprotection reaction of the amino group, formula (9) A compound represented by the formula, or a salt thereof [wherein PG ２ PG ３ and PG ４ This is synonymous with the above. The process of manufacturing [ ].

[0037] [Clause 206] A manufacturing method according to any one of Clauses 201 to 205, further comprising Step 9 below: Step 9 Formula (9) A compound represented by the formula, or a salt thereof [wherein PG ２ PG ３ and PG ４ This is equivalent to the above. ] is given by formula (L) Tartaric acid derivative represented by the formula [wherein R is C１－３ Alkyl or C １－３ It is an alkoxy group. By subjecting it to salt formation with [formula (10)], formula (10) Compound represented by the formula [wherein PG ２ PG ３ PG ４ And R are the same as above. The process of manufacturing ].

[0038] [Clause 207] A manufacturing method according to any one of Clauses 201 to 206, further comprising Step 10 below: Step 10 Formula (10) Compound represented by the formula [wherein PG ２ PG ３ PG ４ And R is the same as above. By treating ] with phosphoric acid, formula (11c) A process for producing a compound represented by (hereinafter also referred to as an oxosubstituted compound (11c)).

[0039] [Clause 208] The method for producing a compound according to Claim 207, wherein in the reaction of Step 10, phosphoric acid is used in an amount of about 20 to about 60 equivalents relative to the compound represented by formula (10). [Clause 209] The method for producing a compound according to Claim 207 or Claim 208, wherein the reaction of Step 10 is carried out in a solvent containing a nitrile solvent. [Clause 210] The method for producing a compound according to any one of Claims 207 to 209, wherein after the reaction of Step 10 is completed, a boronic acid derivative is added to the system. [Clause 211] The method for producing a compound according to any one of Claims 210, wherein after adding a boronic acid derivative to the system, the compound represented by formula (11c) is crystallized in an acetonitrile-methanol-water system. [Clause 212] The method for producing a compound according to any one of Claims 207 to 211, wherein after obtaining the compound represented by formula (11c) by solid-liquid separation, it is washed with a washing solution containing acetonitrile, methanol, phosphoric acid, and water.

[0040] [Clause 213] A manufacturing method according to any one of Clauses 201 to 204, further comprising Step 11 below: Step 11 Formula (8) Compound represented by the formula [wherein PG ２ PG ３ PG ４ and PG ５This is equivalent to the above. By treating ] with phosphoric acid, formula (11c) A process for producing the compound represented by the symbol.

[0041] [Clause 214] The method for producing a compound according to Clause 213, wherein in the reaction of Step 11, phosphoric acid is used in an amount of about 20 to about 60 equivalents relative to the compound represented by formula (8). [Clause 215] The method for producing a compound according to Clause 213 or Clause 214, wherein the reaction of Step 11 is carried out in a solvent containing a nitrile solvent. [Clause 216] The method for producing a compound according to any one of Clauses 213 to 215, wherein after the reaction of Step 11 is completed, a boronic acid derivative is added to the system. [Clause 217] The method for producing a compound according to Clause 216, wherein after adding a boronic acid derivative to the system, the compound represented by formula (11c) is crystallized in an acetonitrile-methanol-water system. [Clause 218] The method for producing a compound according to any one of Clauses 213 to 217, wherein after obtaining the compound represented by formula (11c) by solid-liquid separation, it is washed with a washing solution containing acetonitrile, methanol, phosphoric acid, and water.

[0042] [Clause 219] A manufacturing method according to any one of Clauses 201 to 218, further comprising Step 12 below: Step 12 Formula (11c) The compound represented by (i) is treated with phosphoric acid in water or an inert solvent containing water, or (ii) is treated with an inert solvent containing water, thereby producing the compound of formula (11a). Compounds represented by and / or formula (11b) A step of producing a compound represented by (hereinafter also referred to as oxosubstituted compound (11b)).

[0043] [Clause 220] The method for producing the compound represented by formula (11c) according to claim 219, wherein in method (i) of the reaction of Step 12, phosphoric acid is used in an amount of about 10 to about 40 equivalents.

[0044] [Clause 220A] The method for producing the compound represented by formula (11a) according to claim 219 or 220, wherein Step 12 further comprises a drying step, the drying being carried out by nitrogen aeration to selectively obtain the compound represented by formula (11a).

[0045] [Clause 221] A manufacturing method according to any one of Clauses 201 to 220, further comprising Step 13 below: Step 13 Formula (11b) By adjusting the humidity of the compound represented by formula (11a), A process of converting to a compound represented by the formula.

[0046] [Clause 222] The manufacturing method according to Clause 221, wherein the humidity control of Step 13 is performed under conditions of approximately 50 RH or higher.

[0047] [Clause 223] A manufacturing method according to any one of Clauses 201 to 222 and 220A, further comprising Step 1 below: Step 1 Formula (1) By subjecting a compound represented by formula (2), or a salt thereof [wherein X is a halogen atom], to the Boc(tert-butoxycarbonyl) conversion of two hydroxyl groups and the t-Bu(tert-butyl) esterification of a carboxyl group, formula (2) A process for producing a compound represented by [wherein X is the same as above].

[0048] [Clause 224] A manufacturing method according to any one of Clauses 201 to 223 and 220A, further comprising Step 2 below: Step 2 Formula (2) By subjecting the compound represented by [wherein X is the same as above] to a selective deprotection reaction of the hydroxyl group at the 6th position, formula (3) A process for producing a compound represented by [wherein X is the same as above].

[0049] [Clause 225] A manufacturing method according to any one of Clauses 201 to 224 and 220A, further comprising Step 3 below: Step 3 Formula (3) A compound represented by formula (K) [wherein X is the same as above] is given by formula (K) Azetidine-3-ol represented by the formula [wherein PG] is an NH group protected azetidine-3-ol. １ is a protecting group for amino groups. By subjecting it to the Mitsunobu reaction with ], formula (4) A compound represented by the formula [wherein X and PG １ This is synonymous with the above. The process of manufacturing [ ].

[0050] [Clause 226] A manufacturing method according to any one of Clauses 201 to 225 and 220A, further comprising Step 4 below: Step 4 Formula (4) A compound represented by the formula [wherein X and PG １ This is equivalent to the above. By subjecting ] to a vinylization reaction, formula (5) Compound represented by the formula [wherein PG １ This is synonymous with the above. The process of manufacturing [ ].

[0051] [Clause 227] A manufacturing method according to any one of Clauses 201 to 226 and 220A, further comprising Step 5 below: Step 5 Formula (5) Compound represented by the formula [wherein PG １ This is equivalent to the above. By subjecting ] to a hydroboration reaction, formula (6) Compound represented by the formula [wherein PG １ PG ２ and PG ３ This is synonymous with the above. The process of manufacturing [ ].

[0052] [Clause 228] A manufacturing method according to any one of Clauses 201 to 227 and 220A, further comprising Step 6 below: Step 6 Formula (6) Compound represented by the formula [wherein PG １ PG ２ and PG ３ This is synonymous with the above. By subjecting ] to a deprotection reaction of the azetidinyl group and converting it to a hydrochloride salt, formula (7) Compound represented by the formula [wherein PG ２ and PG ３ This is synonymous with the above. The process of manufacturing [ ].

[0053] [Item 229] Formula (D) including Step D below An amino acid derivative represented by the formula, or a salt thereof [wherein PG ４ and PG ５ This is synonymous with the above. Manufacturing method: Step D Formula (C) A step of producing an amino acid derivative represented by formula (D), or a salt thereof, by liberating a compound represented by and subjecting it to a protection reaction of the amino group and the imidazolyl group.

[0054] [Clause 230] The manufacturing method according to Clause 229, further comprising Step B and C below: Step B Formula (B) By subjecting a compound represented by formula (C') or a salt thereof to a ring-opening reaction, formula (C') is obtained. Step C: A step to produce a compound represented by formula (C') or a salt thereof, by subjecting the compound represented by formula (C') or a salt thereof to salt formation with L-tartaric acid, thereby producing formula (C) A process for producing the compound represented by the symbol.

[0055] [Item 231] PG １ The manufacturing method according to any one of claims 225 to 228, wherein the group is a benzyloxycarbonyl group.

[0056] [Item 232] PG ２ and PG ３ The boronic acids protected by the following formulas independently represent (Ja), (Jb), (Jc), or (Jd): [In the formula, R １ and R ２ Each of them is independently C １－３ The manufacturing method according to any one of claims 201 to 218, 227, 228, and 231, wherein the structure is represented by [alkyl group]. [Claim 233] PG ２ and PG ３ The boronic acid protected by the following formulas independently (Je) or (Jf): A manufacturing method according to any one of claims 201 to 218, 227, 228, and 231, wherein the structure is represented by [the formula shown].

[0057] [Item 234] PG ４ and PG ５ However, each independently corresponds to the following equation (H) or (I): [In the formula, X ａ , X ｂ , X ｃ , X ｄ , X ｅand X ｆ Each of these is independently a halogen atom or C １－３ A protecting group represented by alkoxy group, where m is an integer of 0 or 1, as described in any one of claims 201 to 218, 229, 230, 232, and 233. [Clause 235] PG ４ and PG ５ However, each is independently represented by the formulas (Ha), (Hb), (Hc), or (Hd): A protecting group represented by the method described in any one of claims 201 to 218, 229, 230, 232, and 233.

[0058] [Clause 236] The method for manufacturing according to any one of Clauses 223 to 226, wherein X is a bromine atom. [Clause 237] The method for manufacturing according to any one of Clauses 206 to 212, wherein R is a methyl group.

[0059] [Item A01] Formula (11a) includes any one of Steps 1 to 13, or two or more manufacturing steps that can be carried out consecutively. A method for producing the compound represented by [the given name].

[0060] [Item 301] Formula (D) or (G): [In the formula, PG ４’ and PG ５’ These are independently expressed by the following formulas (H) or (I): [In the formula, X ａ , X ｂ , X ｃ , X ｄ , X ｅ and X ｆ Each of these is independently a halogen atom or C １－３ An alkoxy group, where m is an integer of 0 or 1. A protecting group represented by ]. An amino acid derivative represented by ] or a pharmaceutically acceptable salt thereof.

[0061] [Item 302] PG ４’ and PG ５’The compound according to item 301 or a pharmaceutically acceptable salt thereof, wherein the protecting groups are each independently a protecting group represented by formula (H). [Item 303] The protecting group of formula (H) is one of the following formulas (Ha), (Hb), (Hc) or (Hd): The compound according to item 301 or 302 or a pharmaceutically acceptable salt thereof, wherein the protecting group is represented by the formula:[

[0062] [Item B01] Formula (20): [In the formula, Y is a hydrogen atom or PG ５” where PG ４” and PG ５” are each independently one of the following formulas (H) or (I): [In the formula, X ａ , X ｂ , X ｃ , X ｄ , X ｅ and X ｆ are each independently a halogen atom or a C １－３ alkoxy group, and m is an integer of 0 or 1. ] The protecting group represented by is such that the boronic acids protected by PG ２′ and PG ３′ are each independently one of the following formulas (Ja), (Jb), (Jc) or (Jd): [In the formula, R １ and R ２ are each independently a C １－３ alkyl group. ] The structure represented by is a compound represented by or a pharmaceutically acceptable salt thereof.

[0063] [Item B02] The boronic acids protected by PG ２′ and PG ３′ are each independently one of the following formulas (Je) or (Jf): The compound according to item B01 or a pharmaceutically acceptable salt thereof, wherein the structure is represented by the formula. [Item B03] The compound according to item B01 or B02 or a pharmaceutically acceptable salt thereof, wherein PG ４” and PG ５” are each independently a protecting group represented by formula (H). [Item B04] The protecting group of formula (H) is one of the following formulas (Ha), (Hb), (Hc) or (Hd): A protecting group represented by , the compound described in any one of items B01 to B03, or a pharmaceutically acceptable salt thereof.

[0064] [Item B05] The following formula (10a): [In the formula, PG ２′ PG ３′ and PG ４” R is defined in any one of the terms B01 to B04, and R is C １－３ Alkyl or C １－３ [Item B06] A compound represented by ] is an alkoxy group, the compound described in item B01 or a pharmaceutically acceptable salt thereof.

[0065] [Item C01] A product of formula (11a) manufactured by a method comprising any one of Steps 1 to 13, or two or more manufacturing steps that can be carried out consecutively. A compound represented by the formula.

[0066] [Item D01] A compound represented by formula (20), or a pharmaceutically acceptable acid adduct thereof. [Item D01A] The acid adduct according to Item D01, wherein the pharmaceutically acceptable acid is phosphoric acid or hydrochloric acid. [Item D01B] The acid adduct according to Item D01, wherein the pharmaceutically acceptable acid is phosphoric acid. [Item D02] A phosphate adduct or hydrate obtained by adding 0.5 molecules of phosphoric acid to one molecule of the compound represented by formula (20). [Item D03] A phosphate adduct or hydrate obtained by adding 1 molecule of phosphoric acid to one molecule of the compound represented by formula (20). [Item D04] A hydrochloric acid adduct or hydrate obtained by adding 1 molecule of hydrogen chloride to one molecule of the compound represented by formula (20). [Item D05] The acid adduct or hydrate obtained by adding an acid salt according to any one of Items D02 to D04.

[0067] In this disclosure, one or more of the above features may be provided in combination with or without expressly provided. Further embodiments and advantages of this disclosure will be apparent to those skilled in the art, by reading and understanding the detailed description below as necessary.

[0068] This disclosure makes it possible to provide phosphate, malonate, D-tartrate, phosphate D-tartrate, and hydrochloride phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid (a compound represented by formula (12a) described below (hereinafter also referred to as oxosubstituted compound (12a))) as crystals. These salts and their crystals have excellent β-lactamase inhibitory activity and are useful as prophylactic or therapeutic agents for bacterial infections, either in combination with β-lactam drugs or as monotherapy. Furthermore, the crystal form I of the phosphate salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits high thermal and hygroscopic stability, making it particularly useful as a pharmaceutical product in a wide range of applications, including the manufacturing process, transportation, and storage of the active pharmaceutical ingredient, the formulation process of pharmaceuticals containing the compound, transportation, storage, and administration to patients.

[0069] Methods 1, 2, and 3 allow for the simple, high-yield, and inexpensive production of the crystalline compound (7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylate phosphate) with fewer steps, at a level suitable for large-scale industrial synthesis of pharmaceuticals.

[0070] Figure 1 shows the X-ray powder diffraction pattern of compound 11c (Morphology III), a crystalline phosphate of compound 12a, obtained in Example 11. The x-axis represents the 2θ value, and the y-axis represents the intensity. Figure 2 shows the X-ray powder diffraction pattern of compound 11c (Morphology III Major), a crystalline phosphate of compound 12a, obtained in Example 13. The x-axis represents the 2θ value, and the y-axis represents the intensity. Figure 3 shows the X-ray powder diffraction pattern of compound 11a (Morphology I), a crystalline phosphate of compound 12a, obtained in Example 14. The x-axis represents the 2θ value, and the y-axis represents the intensity. Figure 4 shows the X-ray powder diffraction pattern of compound 11a (Morphology I Major), a crystalline phosphate of compound 12a, obtained in Example 15. The x-axis represents the 2θ value, and the y-axis represents the intensity. Figure 5 shows the X-ray powder diffraction pattern of a mixture of compound 11a and compound 11b (a mixture of forms I and II), which are phosphate crystals of compound 12a, obtained in Example 18. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 6 shows the X-ray powder diffraction pattern of compound 11a (form I), which is a phosphate crystal of compound 12a, obtained in Example 19. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 7 shows the X-ray powder diffraction pattern of compound 17, obtained in Example 27. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 8 shows the X-ray powder diffraction pattern of compound 12a, obtained in Example 29. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 9 shows the X-ray powder diffraction pattern of compound 13a (form IV), which is a malonate crystal (Entry 3) of compound 12a, obtained in Example 32. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 10 shows the X-ray powder diffraction pattern of the malate crystal of compound 12a (Entry 6) obtained in Example 32. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 11 shows the X-ray powder diffraction patterns of the phosphate crystals of compound 12a (Entry 2, 3, 6, 7, and 9) obtained in Example 35. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 12 shows the X-ray powder diffraction pattern of compound 11a (Morphology I), which is a phosphate crystal of compound 12a, obtained in Example 36. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 13 shows the X-ray powder diffraction pattern of compound 11b (Morphology II Major), which is a phosphate crystal of compound 12a, obtained in Example 37. The x-axis represents the 2θ value and the y-axis represents the intensity.Figure 14 shows the X-ray powder diffraction pattern of compound 13b (morphology V Major), which is a crystalline malonate of compound 12a, obtained in Example 38. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 15 shows the X-ray powder diffraction pattern of a mixture of compound 13a and compound 13b (a mixture of morphology IV and morphology V), which are crystalline malonates of compound 12a, obtained in Example 39 before exposure to dry nitrogen. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 16 shows the X-ray powder diffraction pattern of compound 13b (morphology V), which is a crystalline malonate of compound 12a, obtained in Example 39 after exposure to dry nitrogen. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 17 shows the X-ray powder diffraction pattern of compound 14a (morphology VI), which is a crystalline D-tartrate of compound 12a, obtained in Example 40. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 18 shows the X-ray powder diffraction pattern of compound 15a (form VII), which is a crystal of compound 12a's D-tartrate phosphate, obtained in Example 41. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 19 shows the X-ray powder diffraction pattern of compound 16a (form VIII), which is a crystal of compound 12a's diphosphate hydrochloride, obtained in Example 42. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 20 shows the X-ray powder diffraction pattern of compound 11b (form II), which is a crystal of compound 12a's phosphate, obtained in Example 43. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 21 shows the X-ray powder diffraction pattern of compound 11a (form I), which is a crystal of compound 12a's phosphate, obtained by the same method as in Example 14. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 22 shows the X-ray powder diffraction pattern of compound 11c (form III), which is a crystalline phosphate of compound 12a, obtained by the same method as in Example 13. The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 23 shows the X-ray powder diffraction pattern of compound 13a (form IV), which is a crystalline malonate of compound 12a, obtained by the same method as in Example 32 (Entry 3). The x-axis represents the 2θ value and the y-axis represents the intensity. Figure 24 shows the differential scanning calorimetry curve of compound 11a (form I), which is a crystalline phosphate of compound 12a, obtained by the same method as in Example 19. Figure 25 shows the thermogravimetric analysis curve of compound 11a (form I), which is a crystalline phosphate of compound 12a, obtained by the same method as in Example 19.Figure 26 is the dynamic vapor adsorption curve of compound 11a (form I), which is a phosphate crystal of compound 12a, obtained by the same method as in Example 19. Figure 27 is the differential scanning calorimetry curve of compound 11b (form II), which is a phosphate crystal of compound 12a, obtained in Example 44. Figure 28 is the thermogravimetric analysis curve of compound 11b (form II), which is a phosphate crystal of compound 12a, obtained in Example 44. Figure 29 is the dynamic vapor adsorption curve of compound 11b (form II), which is a phosphate crystal of compound 12a, obtained in Example 44. Figure 30 is the differential scanning calorimetry curve of compound 11c (form III), which is a phosphate crystal of compound 12a, obtained by the same method as in Example 11. Figure 31 is the thermogravimetric analysis curve of compound 11c (form III), which is a phosphate crystal of compound 12a, obtained by the same method as in Example 11. Figure 32 is the dynamic vapor adsorption curve of compound 11c (form III), which is a phosphate crystal of compound 12a, obtained by the same method as in Example 11. Figure 33 is the differential scanning calorimetry curve of compound 13a (form IV), which is a malonate crystal of compound 12a, obtained by the same method as in Example 32 (Entry 3). Figure 34 is the thermogravimetric analysis curve of compound 13a (form IV), which is a malonate crystal of compound 12a, obtained by the same method as in Example 32 (Entry 3). Figure 35 is the dynamic vapor adsorption curve of compound 13a (form IV), which is a malonate crystal of compound 12a, obtained by the same method as in Example 32 (Entry 3). Figure 36 is the differential scanning calorimetry curve of compound 13b (form V), which is a malonate crystal of compound 12a, obtained in Example 39. Figure 37 is the thermogravimetric analysis curve of compound 13b (form V), which is a crystalline malonate of compound 12a, obtained in Example 39. Figure 38 is the dynamic vapor adsorption curve of compound 13b (form V), which is a crystalline malonate of compound 12a, obtained in Example 39. Figure 39 is the differential scanning calorimetry curve of compound 14a (form VI), which is a crystalline D-tartrate of compound 12a, obtained in Example 40. Figure 40 is the thermogravimetric analysis curve of compound 14a (form VI), which is a crystalline D-tartrate of compound 12a, obtained in Example 40.Figure 41 is the dynamic vapor adsorption curve of compound 14a (form VI), which is a crystal of D-tartrate of compound 12a, obtained in Example 40. Figure 42 is the differential scanning calorimetry curve of compound 15a (form VII), which is a crystal of D-tartrate phosphate of compound 12a, obtained in Example 41. Figure 43 is the thermogravimetric analysis curve of compound 15a (form VII), which is a crystal of D-tartrate phosphate of compound 12a, obtained in Example 41. Figure 44 is the dynamic vapor adsorption curve of compound 15a (form VII), which is a crystal of D-tartrate phosphate of compound 12a, obtained in Example 41. Figure 45 is the differential scanning calorimetry curve of compound 16a (form VIII), which is a crystal of diphosphate hydrochloride of compound 12a, obtained by the same method as in Example 42. Figure 46 is the thermogravimetric analysis curve of compound 16a (form VIII), which is a crystal of compound 12a hydrochloride diphosphate, obtained by the same method as in Example 42. Figure 47 is the dynamic vapor adsorption curve of compound 16a (form VIII), which is a crystal of compound 12a hydrochloride diphosphate, obtained by the same method as in Example 42. Figure 48 is the MicroED crystal structure of compound 11a (form I), which is a crystal of compound 12a phosphate, performed in Example 54. However, hydrogen atoms are omitted in this MicroED crystal structure. Figure 49 is the chemical structural formula representing the constituent components of the crystal based on the MicroED crystal structure of compound 11a (form I), which is a crystal of compound 12a phosphate, performed in Example 54. Figure 50 is the MicroED crystal structure of compound 11b (form II), which is a crystal of compound 12a phosphate, performed in Example 55 (two molecules of compound 20 are overlapping, and only one molecule is shown). However, hydrogen atoms are omitted in the MicroED crystal structure. Figure 51 is a chemical structural formula showing the constituent components of compound 11b (form II), which is a phosphate salt crystal of compound 12a, as performed in Example 55, based on the MicroED crystal structure of the said crystal. Figure 52 is a MicroED crystal structure of compound 11c (form III), which is a phosphate salt crystal of compound 12a, as performed in Example 56. However, hydrogen atoms are omitted in the MicroED crystal structure.Figure 53 is a chemical structural formula representing the constituent components of compound 11c (form III), which is a crystalline form of compound 12a phosphate obtained in Example 56, based on its MicroED crystal structure. Figure 54 is a MicroED crystal structure of compound 16a (form VIII), which is a crystalline form of compound 12a diphosphate hydrochloride obtained in Example 57. However, hydrogen atoms are omitted in this MicroED crystal structure. Figure 55 is a chemical structural formula representing the constituent components of compound 16a (form VIII), which is a crystalline form of compound 12a diphosphate hydrochloride obtained in Example 57, based on its MicroED crystal structure.

[0071] The present disclosure will be described in more detail below using non-limiting embodiments. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Accordingly, singular articles (e.g., "a," "an," "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. In case of any conflict, this specification (including definitions) shall prevail.

[0072] The present disclosure is described in detail below. 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid has the following structure.

[0073] 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid has been difficult to obtain as a crystalline salt until now. In the development of pharmaceuticals, obtaining the active ingredient as a crystalline substance (also called a crystalline compound, crystalline form, or crystalline polymorph) is important in terms of reproducibility and stability. In particular, crystalline compounds of active ingredients with high thermal and hygroscopic stability are useful as pharmaceuticals in a wide range of processes, including the manufacturing process, transportation, and storage of the active ingredient raw material, the formulation process of the pharmaceutical containing the active ingredient, transportation, storage, and administration to patients. In this disclosure, by adding a specific acid to 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid under specific conditions, it is possible to obtain the compound as a crystalline salt, i.e., a phosphate, malonate, D-tartrate, D-tartrate phosphate, or phosphate hydrochloride. It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction (hereinafter, "XRD"), differential scanning calorimetry (hereinafter, "DSC"), thermogravimetric analysis (hereinafter, "TGA"), dynamic vapor adsorption (hereinafter, "DVS"), diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and liquid-phase and / or solid-phase nuclear magnetic resonance spectroscopy. Furthermore, the water content of crystalline materials can be measured by Karl Fischer analysis. In addition, a three-dimensional structural model can be obtained by X-ray crystal structure analysis of the crystalline material of the compound disclosed herein, i.e., single-crystal structure analysis by X-ray diffraction (see, for example, "A Guide to X-ray Structural Analysis" by Toshio Sakurai, published by Shokabo (1983)), and the absolute configuration of the compound and the component composition ratio of the crystalline material can be confirmed. Furthermore, the absolute configuration of the compound and the component composition ratio of the crystalline material can be confirmed by crystal structure analysis by 3D ED / MicroED (micro-electron diffraction) measurement.

[0074] The phosphate salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid (the compound represented by formula (11)) exists in crystalline polymorphisms, and in this disclosure three crystalline forms (polymorphs) (form I, form II and form III, i.e., the compound represented by formula (11a), the compound represented by formula (11b), and the compound represented by formula (11c)) are specified, but the crystalline forms in this disclosure are not limited to these crystalline forms.

[0075] One aspect of the present disclosure is a crystalline form of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid phosphate (i.e., the compound represented by formula (11a)), characterized as form I.

[0076] Form I of the phosphate salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 9.8 ± 0.2°.

[0077] Form I of the phosphate salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 12.5 ± 0.2°.

[0078] Form I of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 9.8 ± 0.2° and 12.5 ± 0.2°.

[0079] Form I of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 9.8±0.2°, 12.5±0.2°, and 23.5±0.2°.

[0080] Form I of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at at least four diffraction angles (2θ) selected from 9.8±0.2°, 12.5±0.2°, 12.6±0.2°, 14.2±0.2°, 14.6±0.2°, 16.0±0.2°, 20.0±0.2°, 20.2±0.2°, 20.4±0.2°, 21.2±0.2°, 22.6±0.2°, 23.5±0.2°, 24.1±0.2°, and 25.1±0.2°. The crystal is identified by having at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks selected from these fourteen peaks.

[0081] Form I of the phosphate salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same X-ray powder diffraction pattern as the one shown in Figure 21.

[0082] Form I of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits a differential scanning calorimetry curve with an endothermic peak around 221°C. Furthermore, this form I exhibits a differential scanning calorimetry curve substantially identical to the one shown in Figure 24.

[0083] Form I of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits a thermogravimetric analysis curve with a continuous weight loss of approximately 5.6% between approximately 40°C and approximately 105°C. Furthermore, this form I exhibits a thermogravimetric analysis curve substantially identical to the one shown in Figure 25.

[0084] Form I of the phosphate salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same dynamic vapor adsorption curve as the dynamic vapor adsorption curve shown in Figure 26.

[0085] Another aspect of the present disclosure is a crystalline form of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid phosphate (i.e., the compound represented by formula (11b)), characterized as form II.

[0086] Form II of the phosphate salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 5.3 ± 0.2°.

[0087] Form II of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 10.6 ± 0.2°.

[0088] Form II of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 5.3 ± 0.2° and 10.6 ± 0.2°.

[0089] Form II of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 5.3±0.2°, 10.6±0.2°, and 20.1±0.2°.

[0090] Form II of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at at least four diffraction angles (2θ) selected from 5.3±0.2°, 10.6±0.2°, 13.5±0.2°, 15.6±0.2°, 18.1±0.2°, 18.6±0.2°, 20.1±0.2°, 21.6±0.2°, 24.1±0.2°, 25.8±0.2°, and 29.4±0.2°. The crystal is identified by having at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks selected from these eleven peaks.

[0091] Form II of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same X-ray powder diffraction pattern as the one shown in Figure 20.

[0092] Form II of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits a differential scanning calorimetry curve substantially identical to that shown in Figure 27.

[0093] Form II of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same thermogravimetric analysis curve as shown in Figure 28.

[0094] Form II of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same dynamic vapor adsorption curve as the one shown in Figure 29.

[0095] Another aspect of the present disclosure is a crystalline form of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid phosphate (i.e., the compound represented by formula (11c)), characterized as form III.

[0096] Form III of the phosphate salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 9.9 ± 0.2°.

[0097] Form III of the phosphate salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 16.5 ± 0.2°.

[0098] Form III of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 9.9 ± 0.2° and 16.5 ± 0.2°.

[0099] Form III of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 9.9±0.2°, 16.5±0.2°, and 20.6±0.2°.

[0100] Form III of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at at least four diffraction angles (2θ) selected from 9.9±0.2°, 15.4±0.2°, 16.5±0.2°, 20.2±0.2°, 20.6±0.2°, 21.2±0.2°, 22.0±0.2°, 22.9±0.2°, 23.8±0.2°, 24.3±0.2°, and 24.6±0.2°. The crystal is identified by having at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks selected from these eleven peaks.

[0101] Form III of the phosphate salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same X-ray powder diffraction pattern as the one shown in Figure 22.

[0102] Form III of the phosphate salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits a differential scanning calorimetry curve substantially identical to that shown in Figure 30.

[0103] Form III of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same thermogravimetric analysis curve as shown in Figure 31.

[0104] Form III of the phosphate salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same dynamic vapor adsorption curve as shown in Figure 32.

[0105] The malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exists in crystalline polymorphisms, and two crystalline forms (forms IV and V, i.e., the compound represented by formula (13a) and the compound represented by formula (13b)) are specified in this disclosure, but the crystalline forms of this disclosure are not limited to these forms.

[0106] One aspect of the present disclosure is a malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid in crystalline form, characterized as form IV (i.e., the compound represented by formula (13a)).

[0107] Form IV of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 11.7 ± 0.2°.

[0108] Form IV of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 12.3 ± 0.2°.

[0109] Form IV of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 11.7 ± 0.2° and 12.3 ± 0.2°.

[0110] Form IV of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 11.7±0.2°, 12.3±0.2°, and 16.6±0.2°.

[0111] Form IV of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at at least four diffraction angles (2θ) selected from 6.3±0.2°, 11.7±0.2°, 12.3±0.2°, 16.6±0.2°, 20.5±0.2°, 21.3±0.2°, 21.9±0.2°, 22.2±0.2°, 22.8±0.2°, 23.4±0.2°, 25.1±0.2°, and 27.6±0.2°. The crystal is identified by having at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks selected from these twelve peaks.

[0112] Form IV of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same X-ray powder diffraction pattern as shown in Figure 23.

[0113] Form IV of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits a differential scanning calorimetry curve substantially identical to that shown in Figure 33.

[0114] Form IV of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same thermogravimetric analysis curve as shown in Figure 34.

[0115] Form IV of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same dynamic vapor adsorption curve as the one shown in Figure 35.

[0116] Another aspect of the present disclosure is the malonate of the crystalline form of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid (i.e., the compound represented by formula (13b)), characterized as form V.

[0117] Form V of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 10.8 ± 0.2°.

[0118] Form V of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 21.7 ± 0.2°.

[0119] Form V of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 10.8 ± 0.2° and 21.7 ± 0.2°.

[0120] Form V of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 10.8±0.2°, 21.7±0.2°, and 23.0±0.2°.

[0121] Form V of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern having at least four characteristic peaks at at least four diffraction angles (2θ) selected from 8.9±0.2°, 10.8±0.2°, 14.7±0.2°, 15.3±0.2°, 17.0±0.2°, 18.2±0.2°, 21.7±0.2°, 23.0±0.2°, 24.2±0.2°, 25.4±0.2°, 28.4±0.2°, and 28.7±0.2°. The crystal is identified by having at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks selected from these twelve peaks.

[0122] Form V of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same X-ray powder diffraction pattern as the one shown in Figure 16.

[0123] Form V of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits a differential scanning calorimetry curve substantially identical to that shown in Figure 36.

[0124] Form V of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same thermogravimetric analysis curve as shown in Figure 37.

[0125] Form V of the malonate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same dynamic vapor adsorption curve as the one shown in Figure 38.

[0126] The D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid exists in polymorphic form, and one crystalline form (form VI, i.e., the compound represented by formula (14a)) is specified in this disclosure, but the crystalline forms of this disclosure are not limited to this form.

[0127] One aspect of the present disclosure is the D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid in crystalline form, characterized as form VI.

[0128] Form VI of the D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 12.7 ± 0.2°.

[0129] Form VI of the D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 16.5 ± 0.2°.

[0130] Form VI of the D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 12.7 ± 0.2° and 16.5 ± 0.2°.

[0131] Form VI of the D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinin-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 10.4±0.2°, 12.7±0.2°, and 16.5±0.2°.

[0132] Form VI of the D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at at least four diffraction angles (2θ) selected from 10.4±0.2°, 11.8±0.2°, 12.2±0.2°, 12.7±0.2°, 14.6±0.2°, 15.6±0.2°, 16.5±0.2°, 21.1±0.2°, 21.8±0.2°, 22.9±0.2°, 23.5±0.2°, 24.7±0.2°, and 26.6±0.2°. The crystal is identified by having at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks selected from these thirteen peaks.

[0133] Form VI of the D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same X-ray powder diffraction pattern as shown in Figure 17.

[0134] Form VI of the D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits a differential scanning calorimetry curve substantially identical to that shown in Figure 39.

[0135] Form VI of the D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same thermogravimetric analysis curve as shown in Figure 40.

[0136] Form VI of the D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same dynamic vapor adsorption curve as shown in Figure 41.

[0137] The phosphate D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid exists in polymorphic form, and one crystalline form (form VII, i.e., the compound represented by formula (15a)) is specified in this disclosure, but the crystalline forms of this disclosure are not limited to this form.

[0138] One aspect of the present disclosure is the crystalline form of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid, specifically the D-tartrate phosphate salt, characterized as form VII.

[0139] Form VII of the phosphate D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid shows an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 9.6 ± 0.2°.

[0140] Form VII of the phosphate D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid shows an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 23.6 ± 0.2°.

[0141] Form VII of the phosphate D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 9.6 ± 0.2° and 23.6 ± 0.2°.

[0142] Form VII of the phosphate D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 9.6±0.2°, 17.1±0.2°, and 23.6±0.2°.

[0143] Form VII of the phosphate D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at at least four diffraction angles (2θ) selected from 9.6±0.2°, 13.3±0.2°, 17.1±0.2°, 19.8±0.2°, 21.4±0.2°, 22.0±0.2°, 23.6±0.2°, 25.2±0.2°, 26.4±0.2°, 27.4±0.2°, and 28.4±0.2°. The crystal is identified by having at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks selected from these eleven peaks.

[0144] Form VII of the phosphate D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same X-ray powder diffraction pattern as the one shown in Figure 18.

[0145] Form VII of the phosphate D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same differential scanning calorimetry curve as shown in Figure 42.

[0146] Form VII of the phosphate D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same thermogravimetric analysis curve as shown in Figure 43.

[0147] Form VII of the phosphate D-tartrate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same dynamic vapor adsorption curve as the one shown in Figure 44.

[0148] 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid hydrochloride phosphate exists in polymorphisms, and one crystalline form (form VIII, i.e., the compound represented by formula (16a)) is specified in this disclosure, but the crystalline forms of this disclosure are not limited to this form.

[0149] One aspect of the present disclosure is a crystalline form of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid hydrochloride phosphate, characterized as form VIII.

[0150] Form VIII of the hydrochloride phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid shows an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 10.4 ± 0.2°. Form VIII of the hydrochloride phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid shows an X-ray powder diffraction pattern with a characteristic peak at a diffraction angle (2θ) of at least 25.9 ± 0.2°.

[0151] Form VIII of the hydrochloride phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 10.4 ± 0.2° and 25.9 ± 0.2°.

[0152] Form VIII of the hydrochloride phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at diffraction angles (2θ) of at least 10.4±0.2°, 22.7±0.2°, and 25.9±0.2°.

[0153] Form VIII of the hydrochloride phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits an X-ray powder diffraction pattern with characteristic peaks at at least four diffraction angles (2θ) selected from 10.4±0.2°, 14.2±0.2°, 15.5±0.2°, 18.2±0.2°, 19.0±0.2°, 20.7±0.2°, 21.8±0.2°, 22.7±0.2°, 25.2±0.2°, 25.9±0.2°, 27.4±0.2°, 28.3±0.2°, 31.1±0.2°, and 31.6±0.2°. The crystal is identified by having at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks selected from these fourteen peaks.

[0154] Form VIII of the hydrochloride phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same X-ray powder diffraction pattern as the one shown in Figure 19.

[0155] Form VIII of the hydrochloride phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same differential scanning calorimetry curve as shown in Figure 45.

[0156] Form VIII of the hydrochloride phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same thermogravimetric analysis curve as shown in Figure 46.

[0157] Form VIII of the hydrochloride phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits substantially the same dynamic vapor adsorption curve as shown in Figure 47.

[0158] The 2θ value of the X-ray powder diffraction pattern may vary slightly from instrument to instrument or from sample to sample; therefore, the values ​​described herein are not absolute (see Jenkins, R & Snyder, RL 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons 1996; Bunn, CW (1948), C-hemical Crystallography, Clarendon Press, London; Klug, HP & Alexander, LE (1974), X-Ray Diffraction Procedures). Generally, the measurement error of the diffraction angle in X-ray powder diffraction spectra is, for example, about ±0.2° at 2θ, and this level of measurement error should be taken into consideration when examining X-ray powder diffraction data. Furthermore, the intensity may vary depending on the experimental conditions and sample preparation (preferred orientation). In this disclosure, the values ​​shown are those measured using copper emission (Cu Kα1, λ=1.5406 Å, Kα2, λ=1.5444 Å).

[0159] Furthermore, it is known that X-ray powder diffraction patterns with a measurement error of 1 or more may be obtained depending on the measurement conditions (e.g., the equipment or apparatus used). For example, crystal grains larger than 30 microns or with non-uniform aspect ratios may affect the relative intensity of the peaks. Also, the position of reflection may be affected by the precise height at which the sample is placed on the diffractometer and the zero calibration of the diffractometer. The flatness of the sample surface may also have some effect. Therefore, unless otherwise specified, the crystal morphologies of this disclosure are not limited to crystals that yield the X-ray powder diffraction patterns shown in Figures 1 to 23, and any crystal that yields substantially the same X-ray powder diffraction patterns as those shown in these figures is included within the scope of this disclosure.

[0160] Furthermore, a tolerance of ±5°C is permitted for the extrapolation start temperature (Tim) and endothermic peak temperature (Tpm) in differential scanning calorimetry (DSC). The extrapolation start temperature (Tim) in differential scanning calorimetry (DSC) refers to the temperature at the point where the extrapolation lines of the rising portion of the endothermic peak curve and the baseline intersect, and the endothermic peak temperature (Tpm) refers to the temperature at the peak top of the endothermic peak.

[0161] The terms used in this specification are defined below.

[0162] As used herein, unless otherwise specified, the terms “pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” mean a salt prepared from a pharmaceutically acceptable acid (including inorganic and organic acids). Furthermore, “a pharmaceutically acceptable salt as needed” means that it may optionally be a pharmaceutically acceptable salt; for example, in the manufacture of intermediates, a salt that is not pharmaceutically acceptable may be used up to a certain stage. Pharmaceutically acceptable salts include, but are not limited to, phosphates, malonates, tartrates, phosphate phosphates, phosphate hydrochlorides, acetates, alginates, anthranilates, benzenesulfonates, benzoates, camphor sulfonates, citrates, ethensulfonates, formates, fumarates, furons, glucons, glutamates, glucorenates, galacturonates, glycidates, hydrobroms, isethionates, lactates, maleates, malates, mandelates, methanesulfonates, mucinates, nitrates, pamoates, pantothenates, phenylacetates, propions, salicylates, stearates, succinates, sulfanilates, sulfates, and p-toluenesulfonates. In this disclosure, “salt” and “acid” broadly encompass and are mutually interchangeable in form obtained by the reaction of a compound with an acid, unless otherwise specified, and include, for example, non-covalent acid adducts (including acid addition salts that form salts), covalent derivatives (e.g., phosphate esters at the boronic acid moiety), and combinations thereof. In this disclosure, pharmaceutically acceptable salts of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzooxavorinine-8-carboxylic acid (oxosubstituted compound (12a)) are selected from phosphates, malons, D-tartrates, D-tartrate phosphates, and phosphate hydrochlorides. When the oxosubstituted compound (12a) is set to 1, the molar composition ratio of the phosphate of compound (12a) is 2.0 to 3.0 phosphates, and it may be any phosphate within that range.Specifically, these may be 2.0 phosphate, 2.1 phosphate, 2.2 phosphate, 2.3 phosphate, 2.4 phosphate, 2.5 phosphate, 2.6 phosphate, 2.7 phosphate, 2.8 phosphate, 2.9 phosphate, 3.0 phosphate, etc. In one embodiment, if the phosphate is of form I or form II, it may be 2.5 phosphate. In another embodiment, if the phosphate is of form III, it may be 3.0 phosphate. In one embodiment, if the phosphate is of form I or form II, the 2-phosphate component may be a phosphate ester at the boronic acid moiety, and the 0.5-phosphate component may be a phosphate adduct in which one molecule of phosphate is added for every two molecules of the oxo-substituted compound (12a). In one embodiment, if the phosphate is of form III, the 2-phosphate component may be a phosphate ester at the boronic acid moiety, and the 1-phosphate component may be a phosphate adduct in which two molecules of phosphate are added for every two molecules of the oxo-substituted compound (12a). The phosphoric acid content in the phosphate of compound (12a) is in the range of 30 to 50% by weight, for example, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, and 43% by weight. In one embodiment, the content may be in the range of 33 to 43% by weight. As an example of the molar composition ratio of the malonate of compound (12a) when oxosubstituted compound (12a) is set to 1, one example of 1-malonate is given. As an example of the molar composition ratio of the tartrate of compound (12a) when oxosubstituted compound (12a) is set to 1, one example of 1-tartrate is given. Furthermore, the tartrate may be D-tartrate, L-tartrate, and mixtures of them in any ratio (including racemates). When the oxosubstituted compound (12a) is set to 1, the molar composition ratio of the phosphate tartrate (a mixed salt of two different acids consisting of phosphoric acid and tartaric acid) of the compound (12a) is, for example, monophosphate monotartrate. Furthermore, the phosphate tartrate may be D-phosphate tartrate, L-phosphate tartrate, or a mixture of them in any ratio (including racemates). For example, monophosphate 1D-tartrate is a possible example.When the oxosubstituted compound (12a) is set to 1, the molar composition ratio of the hydrochloric acid phosphate (a mixed salt of two different acids consisting of hydrochloric acid and phosphoric acid) of the compound (12a) is, for example, 1-hydrochloric acid 2-phosphate (hydrochloric acid 2-phosphate). In one embodiment, when the 1-hydrochloric acid 2-phosphate is in form VIII, the 2-phosphate component is a phosphate ester at the boronic acid moiety, and the 1-hydrochloric acid component may be a hydrochloric acid phosphate adduct in which one molecule of hydrogen chloride is added per molecule of the oxosubstituted compound (12a).

[0163] Pharmaceutically acceptable salts of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid may be hydrates or solvates, and these are included in the category of pharmaceutically acceptable salts. Examples of hydrates include monohydrate, dihydrate, and trihydrate. For example, if the pharmaceutically acceptable salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid is a phosphate, it may be a 1-3 hydrate. For example, if the phosphate is in form I, it may be a dihydrate. The water content of the phosphate can be in the range of 1 to 10% by weight. For example, if the phosphate is of form I, it can be in the range of 5 to 8% by weight. If the phosphate is of form I, it may be 2.5-phosphate dihydrate. If the phosphate is of form II, it may be 2.5-phosphate anhydrous. If the phosphate is of form III, it may be 3.0-phosphate anhydrous.

[0164] "Purification" refers to any act that increases the purity of a target substance and reduces the concentration of other substances below the concentration before the purification process. Various methods are used for purification, including precipitation, recrystallization, sublimation, distillation, solvent extraction, use of molecular sieves, and application of various chromatography techniques. Filtration using filter paper or Celite is not included in the definition of purification.

[0165] 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid is represented by the following formula (12a), and the compound represented by formula (12c) is interconvertible with the compound represented by formula (12a) by equilibrium reactions in aqueous solutions and in living organisms, and can be biologically equivalent. Furthermore, the compound represented by formula (12c) can exist as a condensate through intermolecular condensation of the phenol group and carboxyl group on the benzene ring with the boronic acid moiety. In addition, the compound represented by formula (12a) can be obtained as an alkali metal salt (e.g., sodium salt) of the compound represented by formula (12b) by reacting it with an alkaline reagent that produces hydroxide ions.

[0166] In this disclosure, when a chemical structural formula of a compound containing a conjugateable double bond shows only one of its multiple possible tautomers, the compound also includes other tautomers that are not shown, and these notations are mutually interchangeable. For example, the compound represented by formula (12a) also includes the compound represented by formula (12d), which is a tautomer at the imidazole moiety, and these notations are mutually interchangeable.

[0167] The phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid (compound represented by formula (11)) includes the compound represented by formula (20) and its phosphate adduct. The hydrochloride phosphate (1-hydrochloride 2-phosphate) of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid (compound represented by formula (16a)) includes the compound represented by formula (20) and its hydrochloride adduct.

[0168] A "halogen atom" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom. Sometimes, "halogen atom" is simply referred to as "halogen."

[0169] "C １－３ "Alkyl" refers to a linear or branched saturated hydrocarbon group with 1 to 3 carbon atoms, and is a "C ３ "Alkyl" refers to an alkyl group with three carbon atoms. The same applies to other numbers. １－３ Specific examples of "alkyl" include, for example, methyl, ethyl, propyl, and 1-methylethyl.

[0170] "C １－３ "alkoxy group" is "C １－３ It means "alkyloxy group". １－３ Preferably, "C" is used as the "alkoxy group". １ It is an "alkoxy group". １－３ Specific examples of "alkoxy groups" include, but are not limited to, methoxy, ethoxy, propoxy, and isopropoxy groups.

[0171] PG １ The "amino group protecting group" shown is a group that can protect the N atom constituting the azetidine ring. PG １ Examples of "amino group protecting groups" shown include the benzyloxycarbonyl group (Z group). PG １ A preferred embodiment of the "amino group protecting group" shown is the benzyloxycarbonyl group (Z group).

[0172] PG ２ and PG ３ The "boronic acid protecting group" shown is a group that can form esters of boronic acid, and examples of protected boronic acids are those of the following formulas (Ja), (Jb), (Jc), or (Jd): [In the formula, R １ and R ２ Each of them is independently C １－３ It is an alkyl group. A structure represented by "[ ]" is an example.

[0173] PG ２ and PG３ A preferred embodiment of the boronic acid protected by the following formula (Je) or (Jf): Examples of structures represented by this diagram include:

[0174] PG ２ and PG ３ A more preferred embodiment of the protected boronic acid is the structure represented by formula (Jf).

[0175] PG ４ The "amino group protecting group" shown is a group that can protect the N atom constituting the imidazole ring. PG ４ and PG ５ Examples of "amino group protecting groups" shown by the following formulas are (H) or (I): [In the formula, X ａ , X ｂ , X ｃ , X ｄ , X ｅ and X ｆ Each of these is independently a halogen atom or C １－３ An example of a protecting group is an alkoxy group, where m is an integer of 0 or 1. [PG] ４ and PG ５ A preferred embodiment of the "amino group protecting group" shown is the protecting group represented by formula (H). PG ４ and PG ５ A more preferred embodiment of the "amino group protecting group" shown by the following formulas is (Ha), (Hb), (Hc), or (Hd): Examples of protecting groups include those represented by the following:

[0176] A preferred embodiment of X is a bromine atom. A preferred embodiment of R is a methyl group.

[0177] The salt or crystals of the disclosed herein can be administered orally or parenterally, either directly or in a suitable dosage form, as a preparation, pharmaceutical or pharmaceutical composition. Specific examples of these dosage forms, but not limited to, include tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. These preparations can also be manufactured by known methods using additives commonly used as pharmaceutical excipients.

[0178] Depending on the purpose, these additives may include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solvents, solubilizers, thickeners, dispersants, stabilizers, sweeteners, flavorings, etc. Specific examples of these additives, though not limited to these, include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, stearyl sodium fumarate, polyethylene glycol, propylene glycol, titanium dioxide, talc, and the like.

[0179] The dosage of the salt or crystals of this disclosure is appropriately selected depending on the target animal, route of administration, disease, patient's age, weight, and symptoms. For example, in the case of oral administration, the lower limit for adults is 0.01 mg (preferably 100 mg) and the upper limit is 10,000 mg (preferably 6,000 mg) per day, and this amount can be administered once a day or in several divided doses.

[0180] The salts or crystals of the disclosed herein are compounds that have inhibitory activity against β-lactamase. Therefore, when used in combination with antibacterial agents, they can be useful preventive or therapeutic agents for bacterial infections. Specific examples of these bacterial infections include sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infections of chronic respiratory diseases, pharyngitis / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infections, lymphangitis / lymphadenitis, secondary infections of wounds, burns and surgical incisions, urinary tract infections, genital infections, eye infections, dental infections, complicated urinary tract infections, complicated intra-abdominal infections, hospital-acquired pneumonia, and ventilator-associated pneumonia.

[0181] The salts or crystals of the Disclosure may be used in combination with at least one agent selected from antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, or antiallergic agents to treat one or more bacterial infections described herein. Preferably, antibacterial agents are included, more preferably β-lactam agents, specifically amoxicillin, ampicillin (pivanpicillin, hetacillin, bacampicillin, methanepicillin, tarampicillin), epicillin, carbenicillin (kalindacillin), ticarcillin, temocillin, azurocillin, piperacillin, mezlocillin, mesilinum (pibmesilinum), sulbenicillin, benzylpenicillin (G), clomethicillin, benzathine benzylpenicillin, procaine benzyl Penicillin, azidocillin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathinephenoxymethylpenicillin, pheneticillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razpenem, cefazolin, cefacetril, cefadroxil, cephalexin, cephaloglysin, cephaloniu Cefaloridine, Cephalothin, Cefapillin, Cefatoridine, Cefazedon, Cefazflu, Cefradin, Ceffloxazine, Ceftezol, Cefaclor, Cephamandol, Cefminox, Cefonisid, Cefolanide, Cefotiam, Cefprodil, Cefbuperazone, Cefuroxime, Cefzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaroxime, Cefdinir, Cefditoren, Cef Etameth, cefmenoxime, cefozidime, cefoperazone, cefotaxime, cefpimisole, cefpyramide, cefpodoxime, cefsulosin, cefteram, ceftibuten, cefthiolen, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirom, cefquinome, ceftobiprole, cephthaloline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefobesin,Examples include aztreonam, tigenonam, carmonam, RWJ-442831, RWJ-333441, or RWJ-333442. Preferably, the β-lactam agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem, or from the group consisting of aztreonam, tigenonam, BAL30072, SYN2416, and carmonam, and more preferably the β-lactam agent is meropenem. The timing of administration of the salts or crystals of the disclosed herein and their therapeutic agents is not limited, and they may be administered to the target patient simultaneously or with a time difference. Alternatively, the salts or crystals of the disclosed herein and their therapeutic agents may be used as a combination. The dosage of these therapeutic agents can be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of the salt or crystals of this disclosure with their therapeutic agents can be appropriately selected depending on the target recipient, route of administration, target disease, symptoms, combination, etc.

[0182] In another aspect of this disclosure, when using a pharmaceutical composition containing an antimicrobial agent such as a β-lactam, salts or crystals of the disclosure may be administered simultaneously or at different times. Such pharmaceutical compositions containing β-lactams are also within the scope of this disclosure and can be used for the treatment or prevention of bacterial infections such as sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infections of chronic respiratory diseases, pharyngitis / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infections, lymphangitis / lymphadenitis, secondary infections of wounds, burns and surgical wounds, urinary tract infections, genital infections, eye infections, dental infections, complicated urinary tract infections, complicated intra-abdominal infections, hospital-acquired pneumonia, and ventilator-associated pneumonia.

[0183] Such pharmaceuticals, formulations, and pharmaceutical compositions can be manufactured by mixing the salt or crystals of the Disclosure and / or additional agents (e.g., antimicrobial agents such as β-lactam antibiotics) together or separately, as a combination or as separate agents, with any appropriate component using any technology known in the art, and can be formulated using any technology known in the art, into appropriate formulations, such as tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and poultices. If the salt or crystals of the Disclosure and / or additional agents (e.g., antimicrobial agents such as β-lactam antibiotics) are prepared as separate agents, they may be provided as a kit of the two agents, or one component may be provided as a monotherapy agent, and the other component (in the case of the salt or crystals of the Disclosure, an additional agent (e.g., an antimicrobial agent such as a β-lactam antibiotic), or in the case of the additional agent (e.g., an antimicrobial agent such as a β-lactam antibiotic), the salt or crystals of the Disclosure) may be provided with instructions (such as a package insert) indicating that the two components should be administered simultaneously or at different times.

[0184] When the salt or crystals of the present disclosure are used as an active ingredient in a pharmaceutical product, they are not intended for use in humans only, but may also be used in other animals (such as cats, dogs, cattle, chickens, and fish).

[0185] The following describes, with examples, the phosphate, malonate, D-tartrate, D-tartrate phosphate and phosphate hydrochloride of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid, as well as methods for producing their crystals, as described below, but the disclosure is not limited thereto.

[0186] The salts and crystals of the present disclosure can be produced, for example, by the manufacturing methods described below. These manufacturing methods can be appropriately modified based on the knowledge of a person proficient in organic synthesis chemistry. In the manufacturing methods described below, the compounds used as raw materials may be their salts, provided that they do not interfere with the reaction.

[0187] In the manufacturing method described below, even if the use of protecting groups is not explicitly stated, if any functional group other than the reaction site changes under the reaction conditions, or if it is unsuitable for post-reaction processing, the target compound can be obtained by protecting the non-reaction site as necessary and deprotecting it after the reaction is complete or after the series of reactions have been carried out. Examples of protecting groups used in these processes are found in the reference (TW Greene and PGM Wuts, “Protective Group in OrganicSynthesis”, 3 rd Conventional protecting groups, as described in Ed., John Wiley and Sons, inc., New York (1999), etc., can be used. Furthermore, the introduction and removal of protecting groups can be carried out by methods commonly used in organic synthesis chemistry (e.g., the methods described in the above-mentioned literature) or by methods similar thereto.

[0188] The starting materials and intermediates used in the following manufacturing method are either commercially available or can be obtained by methods described in public literature or by synthesis from known compounds according to known methods. Furthermore, salts of these starting materials and intermediates may be used, provided they do not hinder the reaction.

[0189] The intermediates and target compounds in the manufacturing method described below can also be converted into other compounds included in this disclosure by appropriately changing their functional groups. The conversion of functional groups in this case can be carried out using methods commonly used in organic synthesis chemistry (e.g., RC Larock, “Comprehensive Organic Transformations”, 2 nd This can be done by the method described in Ed., John Wiley and Sons, inc., New York (1999), or by a similar method.

[0190] In the manufacturing method described below, an inert solvent means a solvent that does not react with the raw materials, reagents, bases, acids, catalysts, ligands, etc. (hereinafter sometimes referred to as "raw materials, etc." used in the reaction) used in the reaction. Furthermore, even if the solvent used in each step reacts with the raw materials, etc. used in the reaction, it can still be used as an inert solvent as long as the desired reaction proceeds and the target compound is obtained.

[0191] Manufacturing method 1

[0192] Manufacturing method 2

[0193] Manufacturing method 3

[0194] Manufacturing method 5

[0195] Manufacturing method 6

[0196] Manufacturing method 4 [Each symbol in the formula has the same meaning as described above.]

[0197] The raw materials used in each step and the intermediates obtained in each step may be solvates or hydrates. Each step is described below.

[0198] Step 1 to Step 10: Manufacturing Method 1 Step 1 In this step, the compound represented by formula (1), or a salt thereof, is subjected to a Boc(tert-butoxycarbonyl) reaction of two hydroxyl groups and a t-Bu(tert-butyl) esterification reaction of a carboxylic acid group to produce the compound represented by formula (2). Both of these Boc and t-Bu esterification reactions may be carried out separately in this disclosure, but can be carried out simultaneously under the following conditions, for example. The reaction is carried out in an inert solvent, in the presence of a base, by Boc... ２ This is carried out by reacting with O. The compound represented by formula (1) can be a commercially available product or one manufactured by a known method. Boc ２O is typically used in amounts of about 2 to about 7 equivalents, preferably about 4 to about 5 equivalents, relative to the compound represented by formula (1) or its salt. Examples of bases include triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine. The base is typically used in amounts of about 1 to about 3 equivalents, preferably about 1 to about 2 equivalents, relative to the compound represented by formula (1) or its salt. Examples of catalysts include N,N-dimethylaminopyridine (DMAP). The catalyst is typically used in amounts of about 0.05 to about 1 equivalent, preferably about 0.05 to about 0.1 equivalents, relative to the compound represented by formula (1) or its salt. The inert solvent is not particularly limited as long as it does not inhibit the reaction, but examples include ether solvents such as tetrahydrofuran (THF). The reaction is usually carried out in a range of about 40 to about 70°C, preferably in a range of about 55 to about 65°C.

[0199] Step 2 In this step, the compound represented by formula (2) is subjected to a selective deprotection reaction of the hydroxyl group at the 6th position to produce the compound represented by formula (3). This reaction is carried out by treating the compound represented by formula (2) with 3,3-diaminopropanamine in an inert solvent. 3,3-diaminopropanamine is usually used in amounts of about 1.0 to about 1.5 equivalents, preferably about 1.0 to about 1.3 equivalents, relative to the compound represented by formula (2). The inert solvent is not particularly limited as long as it does not inhibit the reaction, but examples include aromatic hydrocarbon solvents such as toluene and xylene; and tetrahydrofuran. This reaction is usually carried out in a range of about 10 to about 40°C, preferably in a range of about 20 to about 30°C.

[0200] Step 3 In this step, the compound represented by formula (4) is produced by subjecting the compound represented by formula (3) to a Mitsunobu reaction with NH-protected azetidine-3-ol represented by formula (K). This reaction is carried out in an inert solvent in the presence of the Mitsunobu reagent by reacting the compound represented by formula (3) with NH-protected azetidine-3-ol represented by formula (K). The NH-protected azetidine-3-ol represented by formula (K) can be a commercially available product or one produced by a known method. The NH-protected azetidine-3-ol represented by formula (K) is usually used in an amount of about 1.0 to about 1.5 equivalents, preferably about 1.1 to about 1.2 equivalents, relative to the compound represented by formula (3). Examples of Mitsunobu's reagents include combinations of N,N,N',N'-tetramethylazodicarboxamide (TMAD) and tributylphosphine; and combinations of azodicarboxylic acid diisopropyl and trimethylphosphine. TMAD is typically used in amounts of about 1.0 to 1.5 equivalents, preferably about 1.1 to 1.3 equivalents, relative to the compound represented by formula (3). Tributylphosphine is typically used in amounts of about 1.0 to 1.5 equivalents, preferably about 1.1 to 1.3 equivalents, relative to TMAD. The inert solvent is not particularly limited as long as it does not inhibit the reaction, but examples include aromatic hydrocarbon solvents such as toluene and xylene; and ether solvents such as tetrahydrofuran. The reaction is usually carried out in a range of about 40 to 60°C, preferably about 45 to 55°C.

[0201] Step 4 In this step, the compound represented by formula (4) is subjected to a vinylization reaction to produce the compound represented by formula (5). This reaction is carried out by reacting the compound represented by formula (4) with a vinylizing agent in an inert solvent in the presence of a palladium catalyst, a ligand, and a base. Examples of vinylizing agents include potassium vinyl trifluoroborate. The vinylizing agent is usually used in an amount of about 1.0 to about 2.0 equivalents, preferably about 1.2 to about 2.0 equivalents, relative to the compound represented by formula (4). Examples of palladium catalysts include tris(dibenzylideneacetone)dipalladium(0)(Pd ２ (dba)３ Examples include palladium chloride, palladium acetate, etc. The palladium catalyst is usually used in an amount of about 0.01 to about 0.05 equivalents, preferably about 0.01 to about 0.03 equivalents, relative to the compound represented by formula (4). Examples of ligands include tri-tert-butylphosphonium tetrafluoroborate ( ｔ Bu ３ P.HBF ４ Examples include ), bis(di-tert-butyl)phosphinoferrocene (DTBPF), etc. Ligands are usually used in amounts of about 1 to about 4 equivalents, preferably about 1 to about 2 equivalents, relative to the palladium catalyst. Examples of bases include N,N-diisopropylethylamine (DIPEA), etc. Bases are usually used in amounts of about 2 to about 7 equivalents, preferably 4 to 5 equivalents, relative to the compound represented by formula (4). The reaction may be carried out in the presence of dibutylhydroxytoluene (BHT). BHT is usually used in amounts of about 5 to about 20 equivalents, preferably about 5 to about 10 equivalents, relative to the palladium catalyst. The inert solvent is not particularly limited as long as it does not inhibit the reaction, but examples of aprotic solvents include N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), etc. The reaction is usually carried out in the range of about 40 to about 80°C, preferably in the range of about 55 to about 75°C.

[0202] Step 5 In this step, the compound represented by formula (5) is subjected to a hydroboration reaction to produce the compound represented by formula (6). This reaction is carried out by reacting the compound represented by formula (5) with a boronic acid derivative in an inert solvent in the presence of copper(I) chloride, a phosphine derivative, and a base. Examples of boronic acid derivatives include bis(pinacolato)diborone and bis(catecolato)diborone. The boronic acid derivative is usually used in an amount of about 1.0 to about 2.0 equivalents, preferably about 1.0 to about 1.2 equivalents, relative to the compound represented by formula (5). The copper(I) chloride is usually used in an amount of about 0.005 to about 0.1 equivalents, preferably about 0.005 to about 0.02 equivalents, relative to the compound represented by formula (5). Examples of phosphine derivatives include triphenylphosphine and tri-tert-butylphosphonium tetrafluoroborate. ｔ Bu ３ P.HBF ４ Examples include the following. The phosphine derivative is usually used in an amount of about 0.5 to about 2.0 equivalents, preferably about 1.0 to about 1.2 equivalents, relative to the copper catalyst. Examples of bases include potassium tert-butoxide and sodium tert-butoxide. The base is usually used in an amount of about 1 to about 100 equivalents, preferably about 5 to about 20 equivalents, relative to the copper catalyst. The inert solvent is not particularly limited as long as it does not inhibit the reaction, but examples include alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran (THF); and acetonitrile. The reaction is usually carried out in a range of about 0 to about 50°C, preferably in a range of about 20 to about 30°C.

[0203] Step 6 In this step, the compound represented by formula (6) undergoes a deprotection reaction of the azetidinyl group (protecting group PG １ The compound represented by formula (7) is produced by subjecting it to removal of the azetidinyl group and converting it to a hydrochloride salt. In this step, the protecting group PG １ Depending on the type and the reaction conditions of the deprotection reaction, the deprotection reaction and the conversion to hydrochloride salt may be carried out simultaneously in the same reaction system, or they may be carried out separately and subsequently. For example, the protecting group PG of the azetidinyl group １However, in the case of a benzyloxycarbonyl group (Z group), the deprotection reaction of the azetidinyl group is carried out by subjecting the compound represented by formula (6) to a catalytic hydrogenation reaction using Pd / C. This reaction can be carried out according to known methods. In this case, for example, an aqueous hydrochloric acid solution can be present in the catalytic hydrogenation reaction system to deprotection and conversion to a hydrochloride salt simultaneously.

[0204] Step 7 In this step, the compound represented by formula (8) is produced by subjecting the compound represented by formula (7) to a condensation reaction with an amino acid derivative represented by formula (D), or a salt thereof. This reaction is carried out in an inert solvent in the presence of a condensing agent by reacting the compound represented by formula (7) with an amino acid derivative represented by formula (D), or a salt thereof. The amino acid derivative represented by formula (D), or a salt thereof, is usually used in an amount of about 1.0 to about 2.0 equivalents, preferably about 1.0 to about 1.2 equivalents, relative to the compound represented by formula (7). The condensing agent is not particularly limited as long as the reaction proceeds, but examples include O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), (hydroxyimino)cyanoethyl acetate (Oxima), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), N,N-carbonyldimidazole (CDI), 1H-benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), propylphosphonic anhydride (T3P), etc. The condensing agent is usually used in an amount of about 1.0 to about 2.0 equivalents, preferably about 1.1 to about 1.3 equivalents, relative to the compound represented by formula (7). The reaction is preferably carried out in the presence of a base, and examples of bases include N,N-diisopropylethylamine (DIPEA) and triethylamine (TEA). The base is typically used in an amount of about 2.0 to about 4.0 equivalents, preferably about 3.0 to about 3.5 equivalents, relative to the compound represented by formula (7). The inert solvent is not particularly limited as long as it does not inhibit the reaction, but examples include amide solvents such as dimethylacetamide (DMA) and dimethylformamide (DMF); aromatic hydrocarbon solvents such as toluene and xylene; nitrile solvents such as acetonitrile; ether solvents such as tetrahydrofuran (THF) and methyl tert-butyl ether; and ester solvents such as ethyl acetate and isopropyl acetate. The reaction is usually carried out in a range of about -5°C to about 40°C, preferably in a range of about -5°C to about 5°C.

[0205] Step 8 In this step, the compound represented by formula (8) undergoes a deprotection reaction of the amino group (protecting group PG５ By subjecting it to removal of the amino group PG, a compound represented by formula (9) or a salt thereof is produced. For example, the protecting group PG of the amino group ５ However, in the case of a trityl group (Tr group), the reaction is carried out by treatment with trifluoroacetic acid (TFA) in an inert solvent. This reaction can be carried out according to known methods.

[0206] Step 9 In this step, the compound represented by formula (10) is produced by subjecting the compound represented by formula (9), or a salt thereof, to salt formation with the tartaric acid derivative represented by formula (L). The compound represented by formula (10) is a diastereomer salt formed by the optically active free amine compound represented by formula (9) and the optically active tartaric acid derivative represented by formula (L). It is a chemically stable and easy-to-handle manufacturing intermediate that exhibits excellent properties for maintaining and improving optical purity. This reaction is carried out by mixing the compound represented by formula (9), or a salt thereof, with the tartaric acid derivative represented by formula (L) in an inert solvent. Examples of the tartaric acid derivative represented by formula (L) include (-)-O,O'-di-p-toluyl-L-tartaric acid (L-DTTA), in which R is methyl, and (-)-O,O'-di-p-methoxyphenyl-L-tartaric acid, in which R is methoxy. The tartaric acid derivative represented by formula (L) is usually used in an amount of about 0.5 to about 2.0 equivalents, preferably about 0.9 to about 1.2 equivalents, relative to the compound represented by formula (9) or its salt. To suppress the transesterification reaction with the tartaric acid derivative on boron, the reaction is preferably carried out in the presence of pinacol. The pinacol is usually used in an amount of about 1.0 to about 2.0 equivalents, preferably about 1.5 to about 2.0 equivalents, relative to the compound represented by formula (9) or its salt. The inert solvent is not particularly limited as long as it does not inhibit the reaction, but examples include alcohol solvents such as methanol and ethanol; and aromatic hydrocarbon solvents such as toluene and xylene. Mixing and crystallization are usually carried out in a range of about -5 to about 30°C, preferably in a range of about -5 to about 20°C.

[0207] Step 10 In this step, the compound represented by formula (10) is treated with phosphoric acid to produce the compound represented by formula (11c). The compound represented by formula (11c) is the crystalline form III of the phosphate salt of the compound represented by formula (12a). The reaction is carried out by mixing the compound represented by formula (10) with phosphoric acid in an inert solvent. For example, about 20 equivalents or more, or about 30 equivalents or more, of phosphoric acid is used relative to the compound represented by formula (10), and usually about 20 to about 60 equivalents, preferably about 30 to about 50 equivalents. The reaction is carried out in an inert solvent, but it is preferable to carry it out in a solvent containing a nitrile solvent. Examples of nitrile solvents include acetonitrile. In addition to the nitrile solvent, water, methanol, and ethanol may also be included. Protecting group PG ４ Triphenyl cation (or PG) is a by-product derived from this. ４ To efficiently capture its analogues depending on the type, the reaction may be carried out in the presence of triethylsilane. Triethylsilane is usually used in amounts of about 2.0 to about 5.0 equivalents, preferably about 4.0 to about 5.0 equivalents, relative to the compound represented by formula (10). To complete the deprotection of the boronic acid, it is preferable to add a boronic acid derivative to the system after the reaction is complete. Examples of boronic acid derivatives include alkylboronic acids such as methylboronic acid and isopropylboronic acid; and arylboronic acids such as phenylboronic acid. Boronic acid derivatives are usually used in amounts of about 1 to about 10 equivalents, preferably about 3 to about 8 equivalents, relative to the compound represented by formula (10). After the addition of the boronic acid derivative, the reaction solution is subjected to crystallization. To obtain the target compound represented by formula (11c) as crystals in good yield and effectively, crystallization can be carried out, for example, in an acetonitrile-methanol-water system. Mixing is usually carried out in the range of about 30 to about 50°C, preferably in the range of about 30 to about 40°C. Crystallization is usually carried out in the range of about 10 to about 30°C, preferably in the range of about 15 to about 25°C. After obtaining the crystals by solid-liquid separation, they can be effectively washed with a washing solution containing, for example, acetonitrile, methanol, phosphoric acid, and water.

[0208] Step 11: Manufacturing Method 2 In this step, the compound represented by formula (8), which can be obtained in Step 7, is treated with phosphoric acid to produce the compound represented by formula (11c). The compound represented by formula (11c) is the crystalline form III of the phosphate salt of the compound represented by formula (12a). This step can be carried out in the same manner as described in Step 10.

[0209] Steps 12-13: Manufacturing Method 3 Step 12 (Crystalization Method) In this step, the compound represented by formula (11c) obtained in Step 10 is treated with phosphoric acid to produce the compound represented by formula (11a) or the compound represented by formula (11b) or a mixture thereof via a crystallization process. The compound represented by formula (11a) and the compound represented by formula (11b) are crystalline form I and crystalline form II of the phosphate salt of the compound represented by formula (12a), respectively. The reaction is carried out by mixing with phosphoric acid in water or an inert solvent containing water. For the compound represented by formula (11c), for example, about 10 equivalents or more, or about 20 equivalents or more, of phosphoric acid is used, and usually about 10 to about 40 equivalents, preferably about 20 to about 35 equivalents. By adding phosphoric acid, the crystals of the compound represented by formula (11a) and the compound represented by formula (11b) obtained in the reaction system can be controlled to a particle size appropriate for manufacturing. Examples of water-containing inert solvents include mixed solvents of water with methanol, ethanol, acetonitrile, acetone, etc., and the inert solvent is used in a content of about 5 to about 50% (V / V) in the mixed solvent. To accelerate the crystallization rate, the reaction may be carried out in the presence of sodium dihydrogen phosphate. Sodium dihydrogen phosphate is usually used in amounts of about 1 to about 10 equivalents, preferably about 1.5 to about 2.5 equivalents, relative to the compound represented by formula (11c). Mixing and crystallization are usually carried out in a range of about 0 to about 25°C, preferably about 8 to about 14°C. After obtaining the crystals by solid-liquid separation, they can be effectively washed with, for example, methanol, ethanol, acetonitrile, or acetone. This step may further include a drying step. The drying method may be either vacuum drying or nitrogen aeration drying. Depending on the temperature, time, and other conditions during vacuum drying or nitrogen aeration drying, the ratio of compounds represented by formula (11a) and formula (11b) obtained will vary, and either only one form of the compound may be obtained, or a mixture thereof may be obtained. By performing the drying by nitrogen aeration, only the compound represented by formula (11a) can be selectively obtained.This drying process, for example, involves passing nitrogen humidified to approximately 40 to 70% RH at a temperature range of approximately 10 to 30°C, thereby selectively obtaining only the compound represented by formula (11a).

[0210] Step 12 (Slurry Method) In this step, the compound represented by formula (11c) obtained in Step 10 is treated in the presence of an inert solvent containing water to produce the compound represented by formula (11a) or the compound represented by formula (11b) or a mixture thereof, via a slurry suspension. The compound represented by formula (11a) and the compound represented by formula (11b) are crystalline form I and crystalline form II of the phosphate salt of the compound represented by formula (12a), respectively. Examples of the inert solvent containing water include a mixed solvent of water with methanol, ethanol, acetonitrile, acetone, etc., and the water is used in a content of about 1 to about 20% (V / V), preferably in the range of about 5 to about 15% (V / V) in the mixed solvent. This step is usually carried out in the range of about 0 to about 30°C, preferably in the range of about 15 to about 25°C. After obtaining the crystals by solid-liquid separation, they can be effectively washed with, for example, methanol, ethanol, acetonitrile, or acetone. The process may further include a drying process. The drying method may be either vacuum drying or nitrogen aeration drying. Depending on the temperature, time, and other conditions in vacuum drying or nitrogen aeration drying, the ratio of compounds represented by formula (11a) and formula (11b) obtained will vary, and only one form of the compound may be obtained, or a mixture thereof may be obtained. By performing the drying by nitrogen aeration, only the compound represented by formula (11a) can be selectively obtained. For example, by aeration with nitrogen conditioned to about 40 to about 70% RH at a temperature in the range of about 10 to about 30°C, only the compound represented by formula (11a) can be selectively obtained.

[0211] Step 13 In this step, the compound represented by formula (11b) obtained in Step 12 is converted to the compound represented by formula (11a) by humidity control. This humidity control is carried out under conditions of, for example, about 50 RH or more, about 60 RH or more, about 70 RH or more, or about 80 RH or more, usually about 50 to about 90 RH, more preferably about 70 to about 90 RH. This humidity control is usually carried out in the range of about 5 to about 30°C, preferably in the range of about 15 to about 25°C.

[0212] Step 14: Manufacturing Method 5 In this step, the compound represented by formula (12a) is treated with the corresponding acid to produce the compounds represented by formula (11a), formula (11b), formula (13a), formula (13b), or formula (14a). The compounds represented by formula (11a) and formula (11b) are crystalline forms I and II of the phosphate of the compound represented by formula (12a), respectively; the compounds represented by formula (13a) and formula (13b) are crystalline forms IV and V of the malonate of the compound represented by formula (12a), respectively; and the compound represented by formula (14a) is crystalline form VI of the D-tartrate of the compound represented by formula (12a). The reaction to obtain the compounds represented by formula (11a) and / or formula (11b) is carried out by mixing with phosphoric acid in an inert solvent. Phosphoric acid is usually used in amounts of about 3 to about 50 equivalents, preferably about 10 to about 50 equivalents, relative to the compound represented by formula (12a). The inert solvent is not particularly limited as long as it does not inhibit the reaction, but examples include alcohol solvents such as methanol and ethanol; ketone solvents such as acetone; nitrile solvents such as acetonitrile; ether solvents such as tetrahydrofuran (THF); and ester solvents such as ethyl acetate. Mixing and crystallization are usually carried out in the range of about 0 to about 30°C, preferably in the range of about 15 to about 25°C. The reaction to obtain the compound represented by formula (13a) and / or formula (13b) is carried out by mixing with malonic acid in an inert solvent. Malonic acid is usually used in amounts of about 1 to about 10 equivalents, preferably about 1 to about 3 equivalents, relative to the compound represented by formula (12a). The inert solvent is not particularly limited as long as it does not inhibit the reaction, but examples include alcohol solvents such as methanol; and nitrile solvents such as acetonitrile. Mixing and crystallization are usually carried out in the range of about 0 to about 30°C, preferably in the range of about 15 to about 25°C. The reaction to obtain the compound represented by formula (14a) is carried out by mixing with D-tartaric acid in an inert solvent. D-tartaric acid is typically used in amounts of about 1 to about 2 equivalents, preferably about 1 to about 1.2 equivalents, relative to the compound represented by formula (12a). The inert solvent is not particularly limited as long as it does not inhibit the reaction, but it is preferable to carry out the reaction in a solvent containing water.In addition to water, the mixture may contain about 5 to about 50% (V / V) methanol, ethanol, acetonitrile, and / or acetone. Mixing and crystallization are usually carried out in the range of about 0 to about 30°C, preferably in the range of about 15 to about 25°C.

[0213] Step 15: Manufacturing Method 6 In this step, the compound represented by formula (11c) is treated with the corresponding acid to produce the compound represented by formula (15a) or formula (16a). The compounds represented by formula (15a) and formula (16a) are, respectively, crystalline form VII of the phosphate D-tartrate salt (a mixed salt of two different acids consisting of phosphoric acid and D-tartaric acid) of the compound represented by formula (12a) and crystalline form VIII of the hydrochloric acid phosphate salt (a mixed salt of two different acids consisting of hydrochloric acid and phosphoric acid) of the compound represented by formula (12a). The reaction to obtain the compound represented by formula (15a) is carried out by mixing with D-tartaric acid in an inert solvent. D-tartaric acid is usually used in amounts of about 1 to about 2 equivalents, preferably about 1 to about 1.2 equivalents, relative to the compound represented by formula (11c). The inert solvent is not particularly limited as long as it does not inhibit the reaction, but it is preferable to carry out the reaction in a solvent containing water. In addition to water, the mixture may contain about 5 to about 50% (V / V) methanol, ethanol, acetonitrile, and / or acetone. Mixing and crystallization are usually carried out in the range of about 0 to about 30°C, preferably in the range of about 15 to about 25°C. The reaction to obtain the compound represented by formula (16a) is carried out by mixing phosphoric acid and ammonium chloride in an inert solvent. Phosphoric acid is usually used in amounts of about 10 to about 40 equivalents, preferably 20 to 35 equivalents, relative to the compound represented by formula (11c). Ammonium chloride is usually used in amounts of about 1 to about 10 equivalents, preferably about 8 to about 10 equivalents, relative to the compound represented by formula (11c). The reaction is carried out in an inert solvent, preferably in a solvent containing water. In addition to water, the mixture may contain about 5 to about 50% (V / V) methanol, ethanol, acetonitrile, and / or acetone. Mixing and crystallization are usually carried out in the range of about 0 to about 25°C, preferably in the range of about 8 to about 14°C.

[0214] Step A to Step D: Manufacturing Method 4 Step A In this step, a compound represented by formula (A), or a salt thereof, is subjected to a hydantoinization reaction to produce a compound represented by formula (B), or a salt thereof. This reaction is carried out by reacting the compound represented by formula (A), or a salt thereof, with a cyanating agent and an ammonium salt in an inert solvent. The compound represented by formula (A), or a salt thereof, can be a commercially available product or one produced by a known method. Examples of cyanating agents include potassium cyanide and sodium cyanide. Hydrogen cyanide may also be used in the presence of an alkali. The cyanating agent is usually used in an amount of about 1 to about 2 equivalents, preferably about 1 to about 1.5 equivalents, relative to the compound represented by formula (A), or a salt thereof. Examples of ammonium salts include ammonium carbonate and ammonium bicarbonate. The ammonium salt is usually used in an amount of about 1 to about 2 equivalents, preferably about 1 to about 1.5 equivalents, relative to the compound represented by formula (A), or a salt thereof. The inert solvent is not particularly limited as long as it does not inhibit the reaction, but examples include water; and alcoholic solvents such as methanol and ethanol. The reaction is usually carried out in the range of about 20 to about 70°C, preferably in the range of about 50 to about 60°C.

[0215] Step B: In this step, the compound represented by formula (B), or a salt thereof, is subjected to a ring-opening reaction to produce the compound represented by formula (C'), or a salt thereof. The ring-opening reaction in this step also serves as kinetic resolution by enzymes, allowing the optically active compound represented by formula (C'), or a salt thereof, to be obtained with high optical purity. This reaction is carried out by an enzymatic reaction using three types of enzymes: hydantoinase (Hase), hydantoin racemase (HRase), and decarbamoylase (DCase). The enzymatic reaction is carried out at a pH of approximately 6 to 8, preferably approximately 6 to 7, and usually within a range of approximately 20 to 50°C, preferably within a range of approximately 35 to 45°C. After the reaction is complete, the pH is adjusted to approximately 4 to 5, and the reaction solution can be separated from the bacterial pellet.

[0216] Step C In this step, the compound represented by formula (C) is produced by subjecting the compound represented by formula (C') or a salt thereof to salt formation with L-tartaric acid. The compound represented by formula (C) is a diastereomer salt formed by the optically active free amine compound represented by formula (C') obtained in Step B and L-tartaric acid. It is a chemically stable and easy-to-handle manufacturing intermediate that exhibits excellent properties for maintaining and improving optical purity. This step can be carried out immediately after the completion of the reaction in Step B by mixing the reaction solution separated in Step B with L-tartaric acid. L-tartaric acid is usually used in an amount of 0.4 to 0.7 equivalents, preferably about 0.5 to about 0.6 equivalents, relative to the compound represented by formula (B) or a salt thereof. Mixing is usually carried out in the range of about 0 to about 20°C, preferably in the range of about 0 to about 10°C. After mixing, the mixture is cooled to about 0 to about 5°C and the target product can be crystallized by adding acetone.

[0217] Step D: In this step, the compound represented by formula (C) is liberated, and the amino group and imidazolyl group are protected (protecting group PG ４ and PG ５By subjecting the compound to the introduction of formula (D), an amino acid derivative represented by formula (D) is produced. In this step, the liberation from the compound represented by formula (C) to the compound represented by formula (C') and the protection reaction of each functional group can be carried out simultaneously in the same reaction system. This reaction is carried out by reacting the compound represented by formula (C) with a protecting agent in an inert solvent in the presence of a liberating agent and a Lewis acid. Examples of liberating agents include N-methylmorpholine (NMM) and triethylamine (TEA). The liberating agent is usually used in amounts of about 3 to about 10 equivalents, preferably about 6 to about 8 equivalents, relative to the compound represented by formula (C). Examples of Lewis acids include zinc chloride. The Lewis acid is usually used in amounts of about 2 to about 5 equivalents, preferably about 3 to about 4 equivalents, relative to the compound represented by formula (C). For example, when the protecting group is a trityl group, chlorotriphenylmethane is used as the protecting agent. The protective agent is typically used in an amount of about 2 to about 5 equivalents, preferably about 3 to about 4 equivalents, relative to the compound represented by formula (C). The inert solvent is not particularly limited as long as it does not inhibit the reaction, but examples include nitrile solvents such as acetonitrile. The reaction is usually carried out in a range of about 5 to about 30°C, preferably in a range of about 5 to about 20°C.

[0218] The present disclosure will be further explained below with reference examples and examples, but these will not limit the present disclosure. Furthermore, they may be modified without departing from the scope of the present disclosure. Note that the compound names shown in the following examples and comparative examples do not necessarily follow IUPAC nomenclature. Compound identification was performed by elemental analysis, mass spectrometry, high-performance liquid chromatography-mass spectrometry (LCMS), infrared absorption (IR) spectrometry, nuclear magnetic resonance (NMR) spectrometry, high-performance liquid chromatography (HPLC), etc.

[0219] The retention times (Rt) of each compound measured under each measurement condition are shown in the table below.

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227] In this specification, the following abbreviations may be used: Me: methyl Et: ethyl iPr: isopropyl tBu, t-Bu, But-t: tert-butyl Ph: phenyl Tr: triphenylmethyl Boc: tert-butoxycarbonyl Boc ２ O: Di-tert-butyl dicarbonate DMAP: N,N-dimethylaminopyridine DBA: Dibenzylideneacetone BHT: Dibutylhydroxytoluene Pin: Pinacol Z: Benzyloxycarbonyl TMAD: N,N,N',N'-tetramethylazodicarboxamide PBu ３ : Tributylphosphine PyBOP: (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphonate Et ３ N: Triethylamine Et ３SiH: Triethylsilane DIPEA: N,N-diisopropylethylamine TFA: Trifluoroacetic acid HCl: Hydrochloric acid Pd / C: Palladium carbon powder L-TA: L-Tartaric acid L-DTTA: (-)-O,O'-di-p-Toluoyl-L-Tartaric acid DMA: N,N-Dimethylacetamide THF: Tetrahydrofuran DMSO: Dimethyl sulfoxide NMP: N-Methylpyrrolidone MeCN: Acetonitrile NMM: N-Methylmorpholine AcOH: Acetic acid CDI: N,N-Carbonyldimidazole wt%: Weight percent. v / w: Abbreviation for volume / weight, indicating the ratio of volume to weight of the substrate. Symbols used in NMR include s for single line, d for double line, t for triple line, q for quadruple line, and m for multi-line. Room temperature (rt, rt) is approximately 10°C to approximately 30°C. The compound represented by formula (Q) is sometimes written as "Compound Q" or "Compound Q" (where Q and Q represent Arabic numerals, uppercase letters, or a combination of numbers and lowercase letters), but these are synonymous, or "Compound Q" and "Compound Q" are different forms of the compound represented by formula (Q). For example, the compound represented by formula (1) is sometimes written as "Compound 1" or "Compound 1", the compound represented by formula (A) is sometimes written as "Compound A" or "Compound A", and the compound represented by formula (11a) is sometimes written as "Compound 11a" or "Compound 11a".

[0228] Example 1: Method for producing tert-butyl 3-bromo-2,6-bis[(tert-butoxycarbonyl)oxy]benzoate (Compound 2) 3-Bromo-2,6-dihydroxybenzoic acid (compound 1,98.6 kg) and DMAP (5.12 kg) were added to the reaction vessel, and THF (351.3 kg) was added and dissolved at 15–30°C. Et3N (51.3 kg) was added dropwise at 20–40°C. A Boc2O THF solution (prepared by dissolving Boc2O (423.0 kg) in THF (351.4 kg)) prepared in a separate vessel was added dropwise to the previous solution at 55–60°C, and the progress of the reaction was confirmed by HPLC. The reaction mixture was cooled to 0–10°C, and heptane (269.5 kg) and 10% potassium bisulfate aqueous solution (728.4 kg) were added sequentially. The reaction mixture was heated to 20–30°C, separated, and the aqueous layer was removed. Water (493.5 kg) was added to the organic layer, and the aqueous layer was removed by liquid-liquid separation. The organic layer was concentrated to 2.5 v / w, and then heptane (270.5 kg) was added. The organic layer was concentrated to 2.5 v / w, and then ethanol (78.2 kg) was added. Heptane (270.5 kg) was added over 4 hours at 20–30°C. The mixture was stirred at the same temperature for 1 hour, and then cooled to 0°C. The mixture was stirred at 0°C for 2 hours, and solid-liquid separation was performed. The obtained wet material was washed with pre-cooled heptane (345.2 kg), dried under reduced pressure, and compound 2 was obtained as a white solid in a quantity of 172.1 kg with a purity of 99.9 area by HPLC. 1 H NMR(400MHz, CDCl3) δ 7.62(d, J=8.5Hz, 1H), 7.04 (d, J=8.5Hz, 1H), 1.56 (s, 9H), 1.55 (s, 9H), 1.53 (s, 9H)

[0229] Example 2: Method for producing tert-butyl 3-bromo-2-[(tert-butoxycarbonyl)oxy]-6-hydroxybenzoate (Compound 3) tert-butyl 3-bromo-2,6-bis[(tert-butoxycarbonyl)oxy]benzoate (compound 2, 152.8 kg) and toluene (625.1 kg) were charged into a reaction vessel and completely dissolved. 3,3-diaminopropanamine (38.1 kg) was added dropwise at 20-30°C. The equipment used for dropwise addition was washed with toluene (39.6 kg), and the washings were also added. The reaction mixture was stirred at the same temperature for 3 hours, and the progress of the reaction was confirmed by HPLC. 10% 　 Potassium bisulfate aqueous solution (845.7 kg) was added dropwise, and the mixture was stirred for 1.5 hours. The reaction mixture was allowed to stand, and the aqueous layer was discarded. 10% NaCl aqueous solution (610 kg) was added to the organic layer, and the process of stirring, standing, and discarding the aqueous layer was repeated twice. The organic layer was concentrated to 2.5 v / w, toluene (665.1 kg) was added, and the mixture was concentrated again to 2.5 v / w to obtain a toluene solution of compound 3 (448.0 kg). The HPLC purity of compound 3 was 95.4%, and the content was 25.7%. This solution was used directly in the next step. 1 H NMR(400MHz, CDCl3) δ 11.53 (s, 1H), 7.58 (d, J=9.2Hz, 1H), 6.82 (d, J=9.2Hz, 1H), 1.56 (s, 9H), 1.55 (s, 9H)

[0230] Example 3: Method for producing benzyl 3-{4-bromo-2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]phenoxy}azetidine-1-carboxylate (Compound 4) This reaction was carried out under a strict nitrogen atmosphere. Nitrogen purging was performed by reduced pressure or bubbling. A toluene solution of tert-butyl 3-bromo-2-[(tert-butoxycarbonyl)oxy]-6-hydroxybenzoate (compound 3, theoretical amount 121.5 kg) and Z-azetidinol (71.7 kg) were added to the reaction vessel and nitrogen purged. The reaction mixture was cooled to 0°C, tributylphosphine (75.4 kg) was added dropwise, and the reaction mixture was raised to 10°C (reaction mixture 1). In a separate reaction vessel, TMAD (64.4 kg) and toluene (1196.2 kg) were charged, stirred at 30°C for 1 hour, and then nitrogen purged (reaction mixture 2). At 10°C, reaction mixture 2 was added dropwise to reaction mixture 1 and stirred at the same temperature for 2 hours. The reaction mixture was raised to 50°C and stirred at the same temperature for 15 hours, and the progress of the reaction was confirmed by HPLC. The reaction mixture was cooled to 20°C and filtered. The residue was washed with toluene (664.0 kg), and the filtrate and washings were mixed (mixture). Water (452.8 kg) was added to the mixture and stirred, then allowed to stand and the aqueous layer was removed. The organic layer was washed with water (455 kg) three times. The organic layer was concentrated to 2.5 v / w. Toluene (92.9 kg) was added and the mixture was concentrated to 3.91 w / w. At 30°C, heptane (1246.3 kg) was added, followed by the addition of seed crystals. The mixture was stirred at the same temperature for 7 hours, then cooled to 0°C and stirred for a further 4 hours. The crystallized mass was separated into solid and liquid, and the wet mass was washed with a pre-cooled heptane / toluene mixture (345.3 kg), dried under reduced pressure, and compound 4 was obtained as a white solid in a quantity of 146.4 kg with a purity of 99.9 area by HPLC. 1 H NMR(400MHz, CDCl3) δ 7.49 (d, J=8.8Hz, 1H), 7.29-7.42 (m, 5H), 6.35 (d, J=8.8 Hz, 1H), 5.11 (s, 2H), 4.85-4.98 (m, 1H), 4.37 (dd, J=10.0, 6.4 Hz, 2H), 4.09 (dd, J=10.0, 4.4 Hz, 2H), 1.56 (s, 9H), 1.55 (s, 9H)

[0231] Example 4: Method for producing benzyl 3-{2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-vinylphenoxy}azetidine-1-carboxylate (Compound 5) This reaction was carried out under a strict nitrogen atmosphere. Nitrogen purging was performed by reduced pressure or bubbling. BHT (4.70 kg), purified water (1.06 kg), DMSO (587.1 kg), NMP (586.9 kg), benzyl 3-{4-bromo-2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]phenoxy}azetidine-1-carboxylate (compound 4, 117.5 kg), potassium vinyl trifluoroborate (41.1 kg), and DIPEA (131.5 kg) were added to the reaction vessel, and nitrogen purging was performed. Under a nitrogen stream, P(t-Bu)3・HBF 4 (2.35 kg) and Pd2(dba)3 (1.88 kg) were added. The reaction mixture was heated to 70°C and stirred for 3 hours, and the reaction was confirmed to be progressing by HPLC. The reaction mixture was cooled to 10°C, and toluene (1021.4 kg) and water (1172.8 kg) were added sequentially. The reaction mixture was heated to 40°C, separated, and the aqueous layer was removed. Water (587 kg) was added at the same temperature, and the separation procedure was repeated five times. At 40°C, activated carbon (17.6 kg) was added to the obtained organic layer, stirred for 1 hour, and then the reaction mixture was filtered. The residue was washed with toluene (293.3 kg). The filtrate and washings were mixed and concentrated to 2.5 v / w. At 30°C, heptane (514.1 kg) and seed crystals were added sequentially, cooled to 0°C, and stirred for 8 hours. The crystallized mass was separated into solid and liquid, washed with a pre-cooled heptane / toluene mixture (246.9 kg), and dried under reduced pressure. Compound 5 was obtained as a white solid at a purity of 98.1 kg, measured by HPLC with a purity of 99.7 area. 1H NMR(400MHz, CDCl3) δ 7.45 (d, J=8.8Hz, 1H), 7.29-7.41 (m, 5H), 6.64 (dd, J=18.0, 11.6 Hz, 1H), 6.44 (d, J=8.8 Hz, 1H), 5.66 (dd, J=17.6, 0.8Hz, 1H), 5.29 (dd, J=11.6, 0.8 Hz, 1H), 5.11 (s, 2H), 4.88-5.01 (m, 1H), 4.37 (dd, J=10.8, 6.4 Hz, 2H), 4.09 (dd, J=10.4, 4.0 Hz, 2H), 1.56 (s, 9H), 1.52 (s, 9H)

[0232] Example 5: Method for producing benzyl 3-{2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]phenoxy}azetidine-1-carboxylate (Compound 6) Under a nitrogen atmosphere, benzyl 3-{2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-vinylphenoxy}azetidine-1-carboxylate (compound 5, 86.0 kg), B2Pin2 (45.6 kg), PPh3 (0.43 kg), t-BuOK (1.81 kg), and CuCl (172.3 g) were added to the reaction vessel. The vessel was purged with nitrogen. Methanol (340.8 kg) and THF (153.2 kg) were added, and the reaction mixture was cooled to 0°C. Nitrogen purging under reduced pressure was carried out at the same temperature. The reaction mixture was heated to 25°C, stirred for 1.5 hours at the same temperature, and the progress of the reaction was confirmed by HPLC. Celite (8.6 kg) was added to the reaction mixture, methanol (677.9 kg) was added dropwise, and the mixture was stirred for 1 hour at the same temperature. Activated carbon (8.6 kg) was added to the reaction mixture and stirred for another 30 minutes. The reaction mixture was then filtered, and the residue was washed with methanol (409.0 kg). The filtrate and washings were mixed and concentrated under reduced pressure to 5 v / w. Isopropyl acetate (iPrOAc) was added, the solvent was replaced, and the concentration was adjusted to 13 v / w. The resulting solution was sequentially washed with water (344 1 kg, 259.1 kg). iPrOAc (749.8 kg) was added to the resulting organic layer and concentrated to 2.5 v / w. The solution was heated to 45°C, heptane (585.2 kg) and seed crystals were sequentially added, and the mixture was cooled to 0°C and stirred for 3 hours. The crystallized mass was separated into solid and liquid, washed with a pre-cooled heptane / iPrOAc mixture (246.9 kg), dried under reduced pressure, and compound 6 was obtained as a white solid at a purity of 95.2 kg, measured by HPLC with a purity of 99.4 area. 1 H NMR(400MHz, CDCl3) δ 7.28-7.44 (m, 5H), 7.19 (d, J=8.4 Hz, 1H), 6.39 (d, J=8.4 Hz, 1H), 5.10 (s, 2H), 4.84-4.98 (m, 1H), 4.35 (dd, 0.98-1.15 (m, 2H)

[0233] Example 6: Method for producing tert-butyl 6-[(azetidine-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]benzoate hydrochloride (Compound 7) After purging the reaction vessel with nitrogen, benzyl 3-{2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]phenoxy}azetidine-1-carboxylate (compound 6, 52.55 kg), methanol (367.9 kg), 2 mol / L HCl (42.09 k), and 10% Pd carbon powder (50% wet) (2.53 kg) were charged. The reaction vessel was then purged with hydrogen and stirred at a hydrogen pressure of 150-220 kPa for 5.5 hours. After purging the reaction vessel with nitrogen, 10% Pd carbon powder (50% wet) (1.70 kg) and methanol (7.8 kg) were added. The reaction vessel was purged with hydrogen, stirred at a hydrogen pressure of 150-220 kPa for 7 hours, and the progress of the reaction was confirmed by HPLC. The reaction mixture was filtered, and the residue was washed with methanol (105.0 kg). The filtrate and washings were mixed, toluene (367.9 kg) was added, and the reaction mixture was concentrated under reduced pressure until the volume of the vessel was approximately 310 L. Toluene (376.9 kg) was added, and the reaction mixture was concentrated under reduced pressure until the volume of the vessel was approximately 310 L. Toluene (376.9 kg) was added, and the reaction mixture was concentrated under reduced pressure until the volume of the vessel was approximately 120 L. DMA (26.3 kg) was added to obtain a toluene / DMA mixed solution of compound 7. The content was determined to be 28% by HPLC measurement and used in the next step.

[0234] Example 7: Method for producing tert-butyl 2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]-6-[(1-{(2R)-2-[(triphenylmethyl)amino]-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]benzoate (Compound 8) After purging the reaction vessel with nitrogen, a toluene / DMA mixed solution (76.2 kg) of tert-butyl 6-[(azetidine-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]benzoate hydrochloride (compound 7) obtained in Example 6, compound D (26.1 kg), toluene (12.1 kg), and DMA (50.1 kg) were charged. The reaction mixture was cooled, and a PyBOP / DMA solution prepared by dissolving PyBOP (25.62 kg) in DMA (63.15 kg) was added dropwise at 0°C. DIPEA (17.07 kg) was added dropwise at 0°C, and the mixture was stirred at the same temperature for 2 hours. The reaction was confirmed to have proceeded by HPLC. Toluene (126.4 kg) and 3.4% sodium bicarbonate solution (139.77 kg) were charged, the mixture was heated to 20°C, and the liquid-liquid separation was performed, discarding the aqueous layer. Celite (239.9 kg) was charged into the organic layer, stirred at 0°C for 1 hour, and then filtered. The residue was washed with toluene (63.15 kg), and the filtrate and washings were combined. To the combined solution, 3.4% sodium bicarbonate solution (139.77 kg) was added, and the mixture was separated at 20°C, discarding the aqueous layer. The organic layer was washed twice with water (105.25 kg), and toluene (126.6 kg) was added to the organic layer and concentrated to approximately 240 L to obtain a toluene solution of compound 8. The content was set to 20% by HPLC measurement and used in the next step. 1H NMR (400MHz, CDCl3, observed as a mixture of rotamers) δ 6.93-7.50 (m, 34H), 6.13-6.24 (m,1H), 4.55-4.82 (m,1H), 3.86-4.55 (m, 2H), 3.54-3.86 (m, 2H), 3.37-3.54 (m, 1H), 2.45-2.65 (m, 2H), 1.61 (s, 0.6×9H), 1.54 (s, 0.6×9H), 1.51 (s, 0.4×9H), 1.47 (s, 0.4×9H), 1.20 (s, 0.4×12H), 1.19 (s, 0.6×12H), 0.91-1.12 (m, 2H)

[0235] Example 8: Method for producing tert-butyl 6-[(1-{(2R)-2-amino-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]benzoate (Compound 9) The reaction vessel was purged with nitrogen, and tert-butyl 2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]-6-[(1-{(2R)-2-[(triphenylmethyl)amino]-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]benzoate (compound 8) toluene solution, toluene (13.0 kg), and purified water (0.68 kg) were charged. The reaction mixture was cooled, and a TFA toluene solution prepared from trifluoroacetic acid (21.58 kg) and toluene (37.0 kg) was added dropwise at -10 to -5°C. The mixture was stirred at the same temperature for 1 hour, and the progress of the reaction was confirmed by HPLC. A 16% potassium carbonate aqueous solution (168.51 kg) was added dropwise at -10 to 0°C, the temperature was raised to 20°C, and the liquid-liquid layer was separated and discarded. Ethanol (64.0 kg) and water (170.6 kg) were added, stirred, and the liquid-liquid layer was separated and discarded. Ethanol (213.4 kg) was charged into the organic layer and concentrated under reduced pressure until it reached approximately 305 L. Ethanol (213.4 kg) was charged and concentrated under reduced pressure until it reached approximately 305 L. Ethanol (200.0 kg) and toluene (20.1 kg) were charged to obtain a toluene / ethanol mixed solution of compound 9. The content was determined to be 6% by HPLC measurement and used in the next step. 1 H NMR (400MHz, CDCl3, observed as a mixture of rotamers) δ 7.02-7.51 (m, 18H), 6.72-6.88 (m,1H), 6.28-6.44 (m, 1H), 4.71-5.06 (m,1H), 4.25-4.65 (m, 3H), 3.89-4.25 (m, 2H), 2.42-2.79 (m, 2H), 1.67-1.96 (m, 2H), 1.56 (s, Major×9H), 1.54 (s, Major×9H, minor×9H), 1.52 (s, minor×9H), 1.24 (s, minor×12H), 1.22 (s, Major×12H), 0.99-1.16 (m, 2H)

[0236] Example 9: Method for producing tert-butyl 6-[(1-{(2R)-2-amino-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]benzoate (2R,3R)-2,3-bis[(4-methylbenzoyl)oxy]succinate (Compound 10) Under a nitrogen atmosphere, a toluene / ethanol mixed solution of tert-butyl 6-[(1-{(2R)-2-amino-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]benzoate (compound 9) obtained in Example 8 was sequentially added at 20°C to a toluene / ethanol mixed solution of pinacol (6.22 kg) dissolved in ethanol (35.0 kg) and (-)-O,O'-di-p-toluoyl-L-tartaric acid (L-DTTA) (4.10 kg). L-DTTA (10.09 kg) was dissolved in toluene (2.68 kg) and ethanol (22.11 kg). The resulting solution was added dropwise at 20°C and stirred for 1 hour. The reaction mixture was cooled to 0°C, stirred for 15 hours, and then filtered. The wet material was sequentially washed with a toluene / ethanol mixture (53.28 kg) and ethanol (67.01 kg) twice, dried under reduced pressure, and compound 10 was obtained as a white solid of 41.15 kg with a diastereomer excess of 99.9% de or higher. The cumulative apparent yield from Example 6 onwards was 88%. 1H NMR (400MHz, DMSO-d6, observed as a mixture of rotamers) δ 7.77 (d, J=8.0 Hz, DTTA 4H), 7.29-7.54 (m,11H), 7.25 (d, J=8.0Hz, DTTA 4H), 6.97-7.17 (m, 7H), 6.59-6.76 (m, 1H), 5.57 (s, DTTA, 2H), 4.91-5.18 (m, 2H), 4.24-4.70 (m, 2H), 3.69-4.09 (m, 1H), 2.40-2.50 (m, 2H), 2.33 (s, DTTA 6H), 1.48 (s, isomer A×18H), 1.47 (s, isomer B×9H), 1.39 (s, isomer B×9H), 1.17 (s, 12H), 0.80-0.90 (m, 2H)

[0237] Example 10: Optical resolution of tert-butyl 2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]-6-[(1-{2-[(triphenylmethyl)amino]-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]benzoate Under a nitrogen atmosphere, tert-butyl 6-[(1-{2-amino-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]benzoate (racemic mixture of compound 9) was dissolved in various solvents (10 times the volume) shown in Table 8. The above solution and various acids shown in Table 8 were added to each sample bottle and stirred for 7 days. If crystal formation was confirmed, the solid was filtered off and dried under reduced pressure to confirm its quality. The results are shown in Table 8.

[0238]

[0239] Example 11: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11c) The reaction vessel was purged with nitrogen, and tert-butyl 6-[(1-{(2R)-2-amino-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]benzoate (2R,3R)-2,3-bis[(4-methylbenzoyl)oxy]succinate (compound 10,800 g) and acetonitrile (4,385 g) were added. At a temperature below 40°C, 85% phosphoric acid (3,626 g) and purified water (1,040 g) were added, the temperature was raised to 40°C, and the mixture was stirred for 9 hours. The progress of the reaction was confirmed by HPLC. After cooling the reaction mixture to 20°C, acetonitrile (5005 g) was added dropwise and the mixture was stirred for 2 hours. A methylboronic acid methanol solution prepared from methylboronic acid (188.3 g) and methanol (1903 g) was added dropwise and the mixture was stirred overnight. The reaction mixture was filtered, and the resulting wet material was washed with a washing solution prepared by pre-mixing acetonitrile (941 g), methanol (191 g), 85% phosphoric acid (364 g), and purified water (104 g). The wet material was washed three times with acetonitrile water (1681 g) and five times with methanol (2538 g), dried under reduced pressure, and compound 11c was obtained as a white solid, form III crystal in a yield of 371.3 g, with an apparent yield of 87%, HPLC 99.5 area%, and optical purity of 99.8% ee (Figure 1). 1 ¹H NMR (400MHz, D2O-sodium carbonate) δ 7.63-7.79 (m, 1H), 7.09-7.21 (m, 1H), 6.79-6.94 (m, 1H), 5.95-6.08 (m, 1H), 3.91-5.30 (m, 6H), 2.47-2.68 (m, 2H), 0.25-0.47 (m, 2H)

[0240] Example 12: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11c) A toluene solution of tert-butyl 2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]-6-[(1-{(2R)-2-[(triphenylmethyl)amino]-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]benzoate (compound 8), obtained by the same method as in Example 7, was concentrated to dryness using acetonitrile to obtain a concentrated dry solid of compound 8 with a content of 80%. At room temperature, concentrated dry solid of compound 8 (8.00 g), acetonitrile (31.28 g), and purified water (10.40 g) were added to a reaction vessel. Under a nitrogen stream, 85% phosphoric acid (40.91 g) was added dropwise at a temperature below 20°C, and the dropping apparatus was washed with acetonitrile (12.51 g), and the washings were also added. The reaction mixture was raised to 40°C, and after 9 hours, HPLC measurement was performed to confirm the progress of the reaction. The reaction mixture was cooled to 20°C, and acetonitrile (50.05 g) was added dropwise. The mixture was stirred overnight at the same temperature, and a methylboronic acid methanol solution prepared from methylboronic acid (3.61 g) and methanol (19.03 g) was added dropwise, and the mixture was stirred overnight. The reaction mixture was filtered, and the resulting wet material was washed with a washing solution prepared by pre-mixing acetonitrile (9.74 g), methanol (1.98 g), 85% phosphoric acid (3.20 g), and purified water (1.08 g). The wet sample was washed twice with acetonitrile (16.00 g), dried under reduced pressure, and 3.70 g of compound 11c was obtained as pale pink crystals with an apparent yield of 77%, HPLC analysis of 99.2 area%, and optical purity of >99.9%ee. The crystals were confirmed to be morphology III by XRD.

[0241] Example 13: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11c) The reaction vessel was purged with nitrogen, and tert-butyl 6-[(1-{(2R)-2-amino-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]benzoate (2R,3R)-2,3-bis[(4-methylbenzoyl)oxy]succinate (compound 10, 21 g) was added, followed by the sequential addition of acetonitrile (105 mL) and triethylsilane (10.55 mL). At room temperature, a phosphate acetonitrile solution prepared by pre-mixing acetonitrile (42 mL) and 85% phosphoric acid (95 g) was added dropwise to the suspension of compound 10, and the temperature was raised to 40°C and stirred for 5 hours. At the same temperature, a methanol solution of methylboronic acid (9.89 g) was dissolved in methanol (63 mL) and added dropwise over 12 minutes, followed by stirring for 2 hours. The reaction mixture was cooled to 20°C and stirred overnight at the same temperature. The reaction mixture was then filtered, the resulting wet material was washed with acetonitrile (105 mL), and dried under reduced pressure at 40°C. 11.1 g of compound 11c was obtained as white crystals by HPLC at a 98.9 area% level. The crystals were confirmed to be morph III Major (a mixture with other morphs in which the main component is morph III) by XRD (Figure 2). The qNMR content of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid was 51.9%.

[0242] Example 14: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid phosphate (Compound 11a) The reaction vessel was purged with nitrogen, and 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11c, 750 g) and purified water (3000 g) were added. The mixture was stirred at 20°C until completely dissolved. The reaction mixture was cooled, and 85% phosphoric acid (4326 g) was added dropwise at 12°C or below. At 10°C, the seed crystal prepared in Example 15 was added, and an aqueous solution of sodium dihydrogen phosphate prepared from sodium dihydrogen phosphate dihydrate (334.5 g) and purified water (750 g) was added dropwise. The mixture was stirred at the same temperature for 6 days. The temperature was raised to 20°C, stirred for 1 hour, and then the reaction mixture was filtered. The wet sample was washed three times with acetone water (2249 g) and eight times with acetone (1125 g), then dried under reduced pressure. Compound 11a was obtained as white crystals, yielding 703 g, with an apparent yield of 112%, HPLC accuracy of 99.3 area, and optical purity of 99.9% ee. The crystals were confirmed to be morphology I by XRD (Figure 3). 1 ¹H NMR (400MHz, D2O-sodium carbonate) δ 7.63-7.79 (m, 1H), 7.09-7.21 (m, 1H), 6.79-6.94 (m, 1H), 5.95-6.08 (m, 1H), 3.91-5.30 (m, 6H), 2.47-2.68 (m, 2H), 0.25-0.47 (m, 2H) 31 P NMR(243MHz, DMSO-d6) δ0.00, -4.32

[0243] Example 15: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid phosphate (Compound 11a) At 4°C, 1.581 mL of 85% phosphoric acid was added to 6 mL of ethanol to prepare a phosphoric acid-ethanol solution. In a separate container, at room temperature, 300 mg of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11c) was dissolved in 1.5 mL of purified water. At room temperature, the phosphoric acid-ethanol solution was added dropwise to the aqueous solution of compound 11c and stirred for 4 days. The resulting suspension was filtered, washed with 9 mL of ethanol, and dried under reduced pressure at 40°C to obtain 247 mg of compound 11a as a white solid. XRD confirmed that it was morph I Major (a mixture of other morphs with morph I as the main component) (Figure 4). HPLC 98.4 area%. qNMR showed a 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid content of 57.4%, and ion chromatography showed a phosphate content of 35.6%.

[0244] Example 16: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (Compound 11a) Under a nitrogen atmosphere at room temperature, 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid phosphate (compound 11c, 455 mg) was mixed with various organic solvents (4.55 mL) and water (0.45 mL) and stirred overnight. The solid was filtered off, washed with organic solvent, dried under reduced pressure, and then allowed to stand at room temperature and 70-80% humidity. The results are shown in Table 9.

[0245]

[0246] Example 17: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid phosphate (compound 11a and / or 11b) Under a nitrogen atmosphere, 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11c, 100 mg) was mixed with various organic solvents (0.9 mL) and water (0.1 mL), and stirred overnight at 20°C. The solid was filtered off, washed with acetone water (1 / 1), and dried under reduced pressure. The results are shown in Table 10.

[0247]

[0248] Example 18: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 11a and / or 11b) The reaction vessel was purged with nitrogen, and 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11c, 5.00 g) and purified water (20.00 g) were added. The mixture was stirred at 20°C until completely dissolved. The reaction mixture was cooled, and 85% phosphoric acid (29.66 g) was added dropwise at 12°C or below. Seed crystals prepared in Example 15 were added at 10°C, and an aqueous solution of sodium dihydrogen phosphate prepared from sodium dihydrogen phosphate dihydrate (2.29 g) and purified water (5.00 g) was added dropwise. The mixture was stirred at the same temperature for 45 hours. The temperature was raised to 20°C, and after stirring for 1 hour, the reaction mixture was filtered. The wet material was washed three times with acetone water (15.0 g) and twice with acetone (7.5 g), then dried under reduced pressure. Compounds 11a and 11b were obtained as white crystals in 4.44 g, with an apparent yield of 104%, HPLC analysis of 99.4 area, optical purity of 99.9% ee, and a moisture content of 1.25%. The crystals were confirmed to be a mixture of forms I and II by XRD (Figure 5).

[0249] Example 19: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (Compound 11a) A mixture (4.4 g) of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate compound 11a and compound 11b obtained in Example 18 was left to stand at room temperature for 6 days in a glass cabinet humidified to 80% RH with saturated potassium chloride aqueous solution. Compound 11a was obtained as a white crystal with a moisture content of 5.82%. The crystal was confirmed to be a morphological I crystal by XRD (Figure 6).

[0250] Example 20: Method for producing 5-(1H-imidazole-4-yl)imidazolidine-2,4-dione monohydrate (compound B) 1H-imidazole-4-carbaldehyde (compound A, 50.00 g), ammonium carbonate (55.00 g), methanol (250 mL), and water (250 mL) were added to a reaction vessel and stirred. Sodium cyanide (28.05 g) was added at 20–30°C. The temperature was raised to 60°C and stirred for 3 hours, and the progress of the reaction was confirmed by HPLC. The reaction mixture was cooled to 20°C and concentrated under reduced pressure to 350 g. 6 mol / L hydrochloric acid (29.9 g) was added to adjust the pH to 9.8, and the mixture was stirred at 20°C for 30 minutes. The reaction mixture was filtered, the wet material was washed twice with water (250 mL), and dried under reduced pressure. Compound B was obtained as a yellowish-brown solid of 57.99 g, with an apparent yield of 67% and HPLC area%. 1 H NMR(400MHz, DMSO-d6) δ 12.03 (s, 1H), 10.62 (s, 1H), 8.08 (s, 1H), 7.62 (s, 1H), 7.14 (s, 1H), 5.02 (s, 1H)

[0251] Example 21: Method for producing 5-(1H-imidazole-4-yl)imidazolidine-2,4-dione monohydrate (compound B) 1H-imidazole-4-carbaldehyde (compound A, 5.00 g), ammonium bicarbonate (8.22 g), methanol (20 g), water (18 g), and 25% NaOH aqueous solution (9.15 g) were added to a reaction vessel and stirred. Hydrogen cyanide (1.55 g) was added at 20–30°C, and the mixture was stirred at room temperature for 30 minutes. Then the temperature was raised to 60°C and stirred for 3 hours, and the progress of the reaction was confirmed by HPLC. The reaction mixture was cooled to 20°C and concentrated under reduced pressure to 34.6 g. Concentrated hydrochloric acid (1.67 g) was added to adjust the pH to 9.7, and the mixture was stirred at 20°C for 30 minutes. The reaction mixture was filtered, the wet material was washed twice with water (25 mL), and dried under reduced pressure. Compound B was obtained as a yellowish-brown solid of 6.27 g, with an apparent yield of 72.5% and HPLC 99.9 area%.

[0252] Preparation Example 1: Method for preparing hydantoinase (Hase)-enriched bacterial cells (International Publication No. 2022 / 172829) Escherichia coli HB101 (pTH104) (FERM BP-4864), a transformant containing the hydantoinase gene derived from Bacillus sp. KNK245 strain (FERRM BP-4863) described in International Publication No. 96 / 20275, was inoculated into 100 mL of culture medium A (16 g tryptone, 10 g yeast extract, 5 g sodium chloride, 100 mg ampicillin, made up to 1 L with deionized water, pH 7.0 before sterilization, however ampicillin is added after sterilization) sterilized in a Sakaguchi flask, and cultured aerobically with shaking at 37°C for 24 hours. This culture medium was centrifuged to obtain 10 mL of hydantoinase-concentrated bacterial cells.

[0253] Preparation Example 2: Method for preparing hydantoin racemase (HRase)-enriched bacterial cells (International Publication No. 2022 / 172829) Eschericia coli HB101 (pBHR001) (FERM BP-10476: Patent No. 5096911), which possesses the hydantoin racemase gene derived from Bacillus sp. KNK519HR strain (FERRM BP-10477), was inoculated into 100 mL of culture medium A sterilized in a Sakaguchi flask and cultured aerobically with shaking at 37°C for 24 hours. This culture solution was centrifuged to obtain 10 mL of hydantoin racemase-enriched bacterial cells.

[0254] Preparation Example 3: Method for Preparing Decarbamoylase (DCase)-Concentrated Cells (International Publication No. 2022 / 172829) Eschericia coli HB101 (pNT4553) (FERM BP-4368), which possesses the decarbamoylase gene derived from Agrobacterium sp. KNK712 strain (FERM BP-1900) with improved heat resistance due to genetic modification, was inoculated into 100 mL of culture medium A sterilized in a Sakaguchi flask and cultured aerobically with shaking at 37°C for 24 hours. This culture was then centrifuged to obtain 10 mL of decarbamoylase-concentrated cells.

[0255] Example 22: Method for producing (2R)-amino(1H-imidazole-4-yl)acetic acid 0.5L-tartrate (compound C) Genetically modified E. coli bacteria expressing three enzymes—hydantoinase (Hase), hydantoin racemase (HRase), and decarbamoylase (DCase)—in large quantities within the same cell were cultured, and 9000 g of culture medium was obtained. The obtained culture medium was centrifuged to obtain 900 g of 10x tri-enzyme concentrated cells. Degassed distilled water (3319.1 g), 0.1 M MnSO4・5H2O (42.2 g), and 5-(1H-imidazole-4-yl)imidazolidine-2,4-dione monohydrate (compound B, 213.0 g) were added to a reaction vessel and heated to 40°C. The 10x tri-enzyme concentrated cells (841.9 g) were added, and the pH was adjusted to 7.8–7.1 with 35% hydrochloric acid (3.8 g), and the mixture was stirred for 38 hours. Hase 10-fold concentrated bacterial cells (80.0 g) and DCase 10-fold concentrated bacterial cells (80.0 g) were added, and the mixture was stirred for 8 hours to allow the reaction to proceed. The reaction solution was cooled to below 4°C, adecanol LG109 (2.4 g) was added, and the pH was adjusted from 7.4 to 2.0 with 35% HCl (232.9 g). The pH was then adjusted to 3.0 with 30% NaOH (32.8 g), and the filtrate and bacterial pellet were separated by centrifugation. Water (636 g) was added to the bacterial pellet and mixed, and the mixture was centrifuged to obtain the filtrate. The filtrates from the two containers were mixed to obtain an aqueous solution of (2R)-amino(1H-imidazole-4-yl)acetic acid with an optical purity of 98.3% ee. The aqueous solution was concentrated under reduced pressure, and the resulting impurities were filtered off. Water was then added to prepare a 10 wt% aqueous solution of (2R)-amino(1H-imidazole-4-yl)acetic acid. The aqueous solution was cooled to 5°C, L-tartaric acid (107.97 g) was added, and the mixture was stirred for 1 hour. Acetone (752.5 g) was added and the mixture was stirred for 2 hours. The reaction mixture was filtered and dried under reduced pressure to obtain crude crystals of compound C. Water (4621 g) was added to the crude crystals (340.15 g) and the mixture was stirred for 1 hour. The resulting impurities were filtered off. Acetone (1430 g) was added to the obtained filtrate at 25°C and stirred for 1 hour. After filtration and drying under reduced pressure, compound C was obtained as a white solid of 150.53 g, with an apparent yield of 53%, and HPLC accuracy of 99.9 area%, 100% denomination. 1H NMR(400MHz, D2O) δ 8.65 (d, J=1.5Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 5.01 (s,1H), 4.58 (s, 1H, TA)

[0256] Example 23: Method for producing (2R)-amino(1H-imidazole-4-yl)acetic acid 0.5L-tartrate (compound C) In a reaction vessel, amino(1H-imidazole-4-yl)acetic acid (compound E, 1.24 kg, containing 19% moisture), L-tartaric acid (531.8 g), distilled water (12002 g), salicylaldehyde (172.6 g), and acetone (3800 g) were sequentially added and stirred at 25°C. 6 mol / L hydrochloric acid (517.0 g) was added, the reaction mixture was heated to 40°C, and stirred for 1.5 hours. It was cooled to 25°C and stirred overnight. It was cooled to 5°C and stirred overnight, and the reaction mixture was filtered. The wet material was sequentially washed with 24% aqueous acetone and acetone, dried under reduced pressure, and compound C was obtained as a white solid of 871.5 g, with an apparent yield of 57% and >99.9% de.

[0257] Example 24: Method for producing (2R)-[(triphenylmethyl)amino][1-(triphenylmethyl)-1H-imidazole-4-yl]acetic acid (compound D) Zinc chloride (619.1 g), acetonitrile (265.9 g), and chlorotriphenylmethane (737.7 g) were charged into a reaction vessel at 20–25°C. The reaction mixture was heated to 30°C, and 0.5 L of (2R)-amino(1H-imidazole-4-yl)acetic acid tartrate (compound C, 143.5 g) was added. The mixture was stirred at 30–35°C for 1 hour, then cooled to 20°C. NMM (334.6 g) was added dropwise at the same temperature, and the mixture was stirred for 1.5 hours. The progress of the reaction was confirmed by HPLC. Water (119.5 g) was added, and the mixture was stirred for another hour. Then, THF (572.0 g) and 28% aqueous ammonia (2014.0 g) were added sequentially, and the mixture was stirred. The reaction mixture was allowed to stand, and the aqueous layer was removed. 6 mol / L hydrochloric acid (2103.9 g) was added to the organic layer, stirred, and allowed to stand to remove the aqueous layer. Acetonitrile (1073 g) and THF (215.0 g) were added to the organic layer, and 6 mol / L hydrochloric acid was added until the pH reached 5. After stirring for 26 hours, the mixture was filtered. The wet material was washed three times with an acetonitrile / THF mixture and once with acetonitrile, then dried under reduced pressure to obtain 261.5 g of compound D as a white solid with an apparent yield of 63%, HPLC 97.3 area%, and 99.9% ee. 1 H NMR(400MHz, CDCl3) δ 7.28-7.40 (m, 16H), 7.12-7.26 (m, 9H), 6.61-6.74 (m,6H), 6.68 (s, 1H), 4.44 (s, 1H)

[0258] Example 25: Method for producing (2S)-amino(1H-imidazole-4-yl)acetic acid 0.5D-tartrate (compound F) In a reaction vessel, amino(1H-imidazole-4-yl)acetic acid (compound E, 61.9 g, containing 19% moisture), D-tartaric acid (26.6 g), distilled water (600.0 g), salicylaldehyde (8.7 g), and acetone (242.5 g) were added sequentially and stirred at 25°C. 6 mol / L hydrochloric acid (28.3 g) was added, and the reaction mixture was heated to 50°C and stirred for 1 hour. It was cooled to 25°C and stirred for a further 24 hours. It was cooled to 5°C and stirred for 3 days, and the reaction mixture was filtered. The wet material was sequentially washed with 24% aqueous acetone and acetone, dried under reduced pressure, and compound F was obtained as a white solid of 43.7 g, with an apparent yield of 57% and >99.9% de.

[0259] Example 26: Method for producing (2S)-[(triphenylmethyl)amino][1-(triphenylmethyl)-1H-imidazole-4-yl]acetic acid (compound G) Zinc chloride (57.1 g) and acetonitrile (600.0 g) were charged into a reaction vessel at 20–25°C. After cooling to 10°C, chlorotriphenylmethane (141.5 g) and (2S)-amino(1H-imidazole-4-yl)acetic acid 0.5D-tartrate (compound F, 30.0 g) were added. The mixture was stirred at the same temperature for 1.5 hours, then NMM (89.8 g) was added dropwise at the same temperature, and the mixture was stirred for 2 hours. The progress of the reaction was confirmed by HPLC. Water (45.7 g) was added and stirred for 10 minutes, then THF (120.0 g) and 28% aqueous ammonia (308.7 g) were added sequentially and stirred. The reaction mixture was allowed to stand at 20°C, and the aqueous layer was removed. THF (120.0 g) and 20% saline (250.0 g) were added at the same temperature, and the mixture was stirred for 1 hour. The reaction mixture was allowed to stand, and the aqueous layer was removed. 6 mol / L hydrochloric acid (92 mL) was added to the organic layer, stirred, and allowed to stand, then the aqueous layer was removed. Acetonitrile (120.0 g) was added to the organic layer, and 28% citric acid (230.3 g) was added until the pH reached 5, and the mixture was stirred overnight. The reaction mixture was cooled to 5°C, aged for 3 hours, and then filtered. The wet mixture was washed once each with acetonitrile / THF / water mixture, MeCN / water mixture, and acetonitrile, dried under reduced pressure, and compound G was obtained as a white solid of 73.2 g with an apparent yield of 92%, HPLC 97.3 area%, and 99.9% ee. 1H NMR(400MHz, CDCl3) δ 7.28-7.40 (m, 16H), 7.12-7.26 (m, 9H), 6.61-6.74 (m,6H), 6.68 (s, 1H), 4.44 (s, 1H)

[0260] Example 27: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid 2-hydrochloride (Compound 17) Under a nitrogen atmosphere at room temperature, phenylboronic acid (92.05 g) was added to the reaction vessel, and then 1 mol / L hydrochloric acid / acetic acid (2671.02 g) was added. After stirring at 20±5℃, compound 6-({1-[2-({tert-butoxycarbonyl}amino)-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabolol-2-yl]ethyl}tert-butyl benzoate (compound 19, 200.00 g) from Reference Example 36 of International Publication No. 2019 / 208797 was added in fractional amounts, and the mixture was washed with 1 mol / L hydrochloric acid / acetic acid (50.0 g). After stirring at 20±5℃ for 3 hours, methanol (398.50 g) and acetonitrile (1173.00 g) were added. Subsequently, acetonitrile (195.50 g) was added dropwise over 15 minutes, and a solid precipitated. After stirring the reaction mixture for 15 minutes, acetonitrile (5669.50 g) was added dropwise over 2 hours, and the mixture was stirred overnight at 20±5℃. The obtained solid was filtered, washed twice with acetonitrile (200.00 g), and dried under reduced pressure at 40℃ to obtain 85.0 g of compound 17 as a white solid. Its amorphous nature was confirmed by XRD measurement (Figure 7).

[0261] Example 28: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a) Under a nitrogen atmosphere at room temperature, 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid 2-hydrochloride (compound 17, 20.0 g) and water (206.5 g) were added and stirred. The resulting suspension was cooled to 5°C and methyl tert-butyl ether (60 g) was added. At the same temperature, a 6.3% disodium hydrogen phosphate aqueous solution, prepared by pre-mixing 93.3 g of disodium hydrogen phosphate aqueous solution with water (120 g), was added dropwise and stirred for 15 minutes. The reaction mixture was allowed to stand, the organic layer was discarded, and the aqueous layer was obtained. At the same temperature, 6.3% disodium hydrogen phosphate aqueous solution (152.19 g) was added dropwise to the aqueous layer over 30 minutes and stirred for 1 hour. The resulting solid was filtered off, washed three times with water (80.00 g), and dried under reduced pressure at 40°C. After absorbing moisture at room temperature, 17.1 g of compound 12a was obtained as a white solid.

[0262] Example 29: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a) Under a nitrogen atmosphere at room temperature, 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11a, 5.0 g) was dissolved in water (25 g). 60 mL of an aqueous solution of disodium hydrogen phosphate, prepared from disodium hydrogen phosphate dodecahydrate (15.8 g) and water (70 mL), was added dropwise, and the resulting suspension was stirred. After 1 hour, the solid was filtered off, washed with water (20 mL), dried under reduced pressure, and allowed to stand at room temperature for 6 days to obtain 2.7 g of compound 12a as a white solid. Amorphous properties were confirmed by XRD (Figure 8).

[0263] Example 30: Investigation of chlorination and crystallization of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a) Crystallization studies were conducted under the conditions shown in Tables 11 and 12. However, crystalline salts could not be obtained in any of these cases.

[0264]

[0265]

[0266] Example 31: Investigation of chlorination and crystallization of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a) In a sample vial, 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a, 100 mg), 2 equivalents of acid additive relative to compound 12a, water (1 mL), and acetonitrile (1 mL) were added and stirred overnight. The precipitated solid was filtered under reduced pressure and dried, and the resulting solid was measured by XRD. The results are shown in Table 13.

[0267]

[0268] Example 32: Investigation of chlorination and crystallization of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (Compound 12a) 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a, 100 mg), 2 equivalents of acid additive relative to compound 12a, methanol (1 mL), and acetonitrile (1 mL) were added to a sample vial and stirred overnight. The precipitated solid was filtered under reduced pressure and dried, and the obtained solid was measured by XRD. The results are shown in Table 14. The XRDs of the crystals obtained in Entry 3 and 6 are shown in Figures 9 and 10.

[0269]

[0270] Example 33: Investigation of chlorination and crystallization of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a) In a reaction vessel, 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a, 100 mg) was suspended in acetonitrile (3 mL). Hydrochloric acid was added, and the mixture was stirred at 25°C for 18 hours. The reaction mixture was filtered, the wet material was washed with a solvent, and dried under reduced pressure to obtain the hydrochloride salt of compound 12a. The results are shown in Table 15.

[0271]

[0272] Example 34: Investigation of chlorination and crystallization of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a) In a reaction vessel, 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a, 100 mg) was suspended in acetonitrile (3 mL). Sulfuric acid was added, and the mixture was stirred at 25°C for 18 hours. The reaction mixture was filtered, the wet material was washed with a solvent, and dried under reduced pressure to obtain compound 18, the sulfate salt of compound 12a. The results are shown in Table 16.

[0273]

[0274] Example 35: Investigation of chlorination and crystallization of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a) In a reaction vessel, 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a, 100 mg) was suspended in various organic solvents (20 v / w to 30 v / w). Phosphoric acid was added, and the mixture was stirred at 25°C for 5 days. The reaction mixture was filtered, the wet material was washed with a solvent, and dried under reduced pressure to obtain solid or crystalline phosphate of compound 12a. The results are shown in Table 17, and the XRD of the obtained crystals is shown in Figure 11.

[0275]

[0276] Example 36: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (Compound 11a) At room temperature, 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a, 200 mg) was suspended in acetonitrile (3.0 mL) and water (1.2 mL). 85% phosphoric acid (2.5 g) was added dropwise, and the mixture was stirred overnight. The resulting solid was filtered, washed twice with 10 mL of acetonitrile, and dried under reduced pressure at 40°C to obtain 220 mg of compound 11a as a white solid. It was confirmed to be morphology I by XRD (Figure 12).

[0277] Example 37: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid phosphate (compound 11b) The reaction vessel was purged with nitrogen, and 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a, 3.47 g), purified water (20.0 g), and 85% phosphoric acid (8.47 g) prepared by the method described in Example 28 were added. The mixture was stirred at 20°C until completely dissolved. The reaction mixture was cooled, and 85% phosphoric acid (23.73 g) was added dropwise at 12°C or below. At 10°C, the seed crystal prepared in Example 15 was added, and an aqueous solution of sodium dihydrogen phosphate prepared from sodium dihydrogen phosphate dihydrate (2.29 g) and purified water (5.0 g) was added dropwise. The mixture was stirred at the same temperature for 3 days. The temperature was raised to 20°C, stirred for 1 hour, and then the reaction mixture was filtered. The wet sample was washed three times with acetone water and twice with acetone, then dried under reduced pressure. 3.95 g of compound 11b was obtained as a white crystal, measured by HPLC at 98.7 area and with an optical purity of 99.8% ee. The crystal was confirmed to be morphology II Major (a mixture with other morphologies in which morphology II is the main component) by XRD (Figure 13).

[0278] Example 38: Investigation of chlorination and crystallization of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a) In a reaction vessel, 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a, 1 g), methanol (13 mL), and acetonitrile (13 mL) were added at room temperature and the mixture was stirred. At an internal temperature of 20°C, malonic acid (0.54 g) was added and the mixture was stirred for 46 hours. The reaction mixture was filtered, the wet material was washed with methanol / acetonitrile = 1 / 1, and dried under reduced pressure to obtain the malonate of compound 12a (compound 13b, 1.01 g) as white crystals of form V Major (a mixture of other forms in which form V is the main component). The XRD is shown in Figure 14.

[0279] Example 39: Investigation of chlorination and crystallization of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a) 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a, 5.0 g), malonic acid (2.69 g), methanol (75 mL), and acetonitrile (75 mL) were added to a reaction vessel and stirred at 25°C for 72 hours. The reaction mixture was filtered, the wet material was washed with methanol / acetonitrile = 1 / 1, and dried under reduced pressure to obtain the malonate of compound 12a as a white crystalline mixture of forms IV and V (Figure 15). The obtained malonate (5.0 g) was aerated with dry nitrogen at 40°C for 24 hours to obtain the malonate of compound 12a (4.72 g) as a white crystalline mixture of form V (Figure 16).

[0280] Example 40: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid D-tartrate (Compound 14a) The reaction vessel was purged with nitrogen, and 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 12a, 1.00 g) and purified water (8.40 g) were added. The mixture was stirred at room temperature to obtain a suspension. An aqueous solution of D-tartaric acid prepared from D-tartaric acid (0.13 g) and purified water (1.68 g) was added at room temperature, and the mixture was stirred at the same temperature for 20 minutes. An aqueous solution of D-tartaric acid prepared from D-tartaric acid (0.21 g) and purified water (2.52 g) was added at room temperature, and the mixture was stirred overnight at the same temperature. The reaction mixture was filtered, the wet material was washed with water (12.6 g), and dried under reduced pressure to obtain 1.25 g of compound 14a as crystals of form VI. Ion chromatography analysis confirmed the presence of 25.5% D-tartrate ions. The XRD results are shown in Figure 17.

[0281] Example 41: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid phosphate D-tartrate (compound 15a) The reaction vessel was purged with nitrogen, and 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11c, 2.00 g) and purified water were added and stirred at room temperature until completely dissolved. An aqueous solution of D-tartaric acid prepared from D-tartaric acid (0.10 g) and purified water (10.48 g) was added at room temperature and stirred overnight at the same temperature. An aqueous solution of D-tartaric acid prepared from D-tartaric acid (0.15 g) and purified water (2.62 g) was added at room temperature and stirred for 4 hours at the same temperature. D-tartaric acid (0.15 g) was added at room temperature and stirred for 4 days. The reaction mixture was filtered, the wet material was washed with water (20.0 g), and dried under reduced pressure to obtain 1.39 g of compound 15a as morphological VII crystals. Ion chromatography analysis confirmed the presence of 21.3% D-tartrate ions and 6.1% phosphate ions. The XRD results are shown in Figure 18.

[0282] Example 42: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid hydrochloride diphosphate (compound 16a) The reaction vessel was purged with nitrogen, and 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11c, 6.00 g) and purified water (18.0 g) were added. The mixture was stirred at 20°C until completely dissolved. The reaction mixture was cooled, and 85% phosphoric acid (43.2 g) was added dropwise at 12°C or below. Seed crystals prepared in Example 15 were added at 10°C, and an aqueous solution of ammonium chloride prepared from ammonium chloride (4.7 g) and purified water (15.0 g) was added dropwise. The mixture was stirred at the same temperature for 20 hours. The temperature was raised to 20°C, and the reaction mixture was filtered. The wet sample was washed four times with ethanol (24.0 g), and 5.35 g of compound 16a was obtained as morphological VIII crystals. Ion chromatography analysis confirmed the presence of 4.7% chloride ions and 26.8% phosphate ions. The XRD results are shown in Figure 19. 1 ¹H NMR (400MHz, D2O-sodium carbonate) δ 7.63-7.79 (m, 1H), 7.09-7.21 (m, 1H), 6.79-6.94 (m, 1H), 5.95-6.08 (m, 1H), 3.91-5.30 (m, 6H), 2.47-2.68 (m, 2H), 0.25-0.47 (m, 2H)

[0283] Example 43: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid phosphate (compound 11b) The reaction vessel was purged with nitrogen, and 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11c, 5.00 g), sodium dihydrogen phosphate dihydrate (1.13 g), and purified water (20.0 g) were added. The mixture was stirred at 20°C until completely dissolved. The reaction mixture was cooled, and 85% phosphoric acid (33.44 g) and purified water (5.00 g) were added at 12°C or below. At 10°C, the seed crystal prepared in Example 15 was added, and the mixture was stirred for 24 hours. An aqueous solution of sodium dihydrogen phosphate prepared from sodium dihydrogen phosphate dihydrate (5.66 g) and purified water (7.50 g) was added dropwise, and the mixture was stirred at the same temperature for 72 hours. The reaction mixture was heated to 20°C and stirred for 5 hours, after which it was filtered. The wet mixture was washed with a mixture of sodium dihydrogen phosphate dihydrate (0.68 g), purified water (3.25 g), and 85% phosphoric acid (3.34 g), then three times with ethanol-water (15.0 g) and twice with ethanol (7.5 g), dried under reduced pressure, and 3.87 g of compound 11b was obtained as white crystals with an apparent yield of 91.6% by HPLC at a 99.1 area percentage. The crystals were confirmed to be morphology II by XRD. The XRD results are shown in Figure 20.

[0284] Example 44: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid phosphate (compound 11b) 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11a, 3.0 g) obtained by the same method as in Example 15 was mixed with ethanol (60 mL) and stirred at room temperature for 24 hours. The resulting suspension was filtered, washed with ethanol (30 mL), and dried under reduced pressure at 40°C to obtain 2.8 g of compound 11b as a white solid. XRD confirmed that it was form II Major (a mixture with other forms in which form II is the main component). Ion chromatography showed a phosphate content of 33.8%.

[0285] Characterization of Crystal Morphology The crystal morphologies of the salts of this disclosure were characterized using various analytical techniques, including X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor adsorption (DVS), using the following procedure.

[0286] Example 45: X-ray powder diffraction (XRD) of crystals of morphology I to morphology VIII. X-ray powder diffraction of crystals of morphology I to morphology VIII was performed using the following method. X-ray powder diffraction: XRD analysis was performed using a diffractometer (Bruker AXS D8 ADVANCE, Bruker, Billerica, Massachusetts, USA) with copper emission (Cu Kα1, λ=1.5406 Å, Kα2, λ=1.5444 Å). The sample was prepared for analysis by placing the powdered sample in the center of a steel holder equipped with a zero background plate. The generator was operated at a voltage of 40 kV and an amperage of 40 mA. The scanning range was 5 to 40° at the diffraction angle 2θ, with a step size of 0.015° and an irradiation time of 48 seconds per step. Data analysis was performed using DIFFRAC. The study was conducted by EVA (Brker, Billerica, Massachusetts, USA).

[0287] Example 46: Differential Scanning Calorimetry (DSC) of Crystals of Forms I to VIII The differential scanning calorimetry of the crystals of Forms I to VIII was carried out by the following method. Differential Scanning Calorimetry: The thermal properties were evaluated using a differential scanning calorimetry (DSC) instrument (DSC2500, TA Instruments, New Castle, DE, USA). Approximately 1 to 10 mg of the solid sample was placed in a standard aluminum pan and heated under a nitrogen purge of 50 mL / min. Data analysis was carried out using Trios version 5.0 (TA Instruments, New Castle, DE, USA).

[0288] Example 47: Thermogravimetric Analysis (TGA) of Crystals of Forms I to VIII The thermogravimetric analysis of the crystals of Forms I to VIII was carried out by the following method. Thermogravimetric Analysis: Thermogravimetric analysis (TGA) was carried out using a TGA instrument (TGA 5500, TA Instruments, New Castle, DE, USA). Approximately 1 to 10 mg of the solid sample was placed in an open aluminum pan and heated at a rate of 10 °C / min under a nitrogen purge of 25 mL / min. Data analysis was carried out using Trios version 5.0 (TA Instruments, New Castle, DE, USA).

[0289] Example 48: Dynamic Vapor Sorption (DVS) of Crystals of Forms I to VIII The dynamic vapor sorption of crystals of Forms I to VIII was carried out by the following method. Dynamic Vapor Sorption: The hygroscopicity was evaluated at room temperature using a dynamic vapor sorption (DVS) instrument (IGAsorp, Hiden Isochema, Warrington, England). Water sorption and desorption were studied at 25 °C over a range of 0 to 95% relative humidity (RH) as a function of RH. The cycle was repeated twice. All experiments were operated in the dm / dt mode (mass variation over time) to determine the equilibration endpoints. The relative humidity in the chamber was increased in steps of 10% RH and held until the solid and the atmosphere reached equilibrium. At this point, the RH was increased by 10% and the process was repeated until 95% RH was reached and equilibration occurred. During this period, the moisture sorption was monitored. For desorption, the relative humidity was reduced in a similar manner to measure a complete sorption / desorption cycle. The cycle was repeated twice. All experiments were operated in the dm / dt mode (mass variation over time) to determine the equilibration endpoints. Approximately 5 to 10 mg of the solid was used. Data analysis was carried out using Hisorp v4.02 (Hiden Isochema, Warrington, England).

[0290] The results of Examples 46 to 48 are shown in Figures 24 to 47.

[0291] Example 49: Stability Evaluation of Crystalline Salt of 7-({1-[(2R)-2-Amino-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic Acid Various crystalline salts were stored for a certain period under the specified storage forms, temperature, and humidity. The quality was analyzed under the conditions described in Method 3 and Method 7. The results are shown in Tables 18 and 19.

[0292]

[0293]

[0294] Example 50: Method for producing tert-butyl 2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]-6-[(1-{(2R)-2-[(triphenylmethyl)amino]-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]benzoate (Compound 8) After purging the reaction vessel with nitrogen, compound D (3.49 g), acetonitrile (5.64 g), and DIPEA (2.29 g) were charged. At 25°C, a solution prepared from CDI (1.11 g) and acetonitrile (2.82 g) was added. The reaction mixture was heated to 40°C and stirred at the same temperature for 2.5 hours. After cooling the reaction mixture to 25°C, a solution of compound 7 prepared from concentrated dry solid (3.00 g) of tert-butyl 6-[(azetidine-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]benzoate hydrochloride (compound 7) obtained in Example 6, toluene (6.35 g), and acetonitrile (3.09 g) was added. The reaction mixture was stirred at 25°C for 3 hours, and the reaction was confirmed to have proceeded by HPLC. Saltwater (16.92 g) was added, the mixture was stirred for 1 hour, and then the solution was separated and the aqueous layer was discarded. The resulting solution was concentrated to dryness, acetonitrile (14.10 g) was added, and the mixture was concentrated again to dryness. Acetonitrile (31.3 g) was added to obtain an acetonitrile solution of compound 8 (29.23 g).

[0295] Example 51: Method for producing tert-butyl 2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]-6-[(1-{(2R)-2-[(triphenylmethyl)amino]-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]benzoate (Compound 8) After purging the reaction vessel with nitrogen, compound D (18.6 g), isopropyl acetate (75 mL), and DIPEA (12.2 g) were charged, and CDI (5.99 g) was added. The reaction mixture was heated to 40°C and stirred at the same temperature for 2.5 hours. After cooling the reaction mixture to 25°C, an isopropyl acetate solution of compound 7, prepared from concentrated dry solid (16.9 g) of tert-butyl 6-[(azetidine-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]benzoate hydrochloride (compound 7) obtained in Example 6 and isopropyl acetate (45.0 g), was added dropwise over 30 minutes. After stirring the reaction mixture at 25°C for 2 hours, the reaction was confirmed to have proceeded by HPLC. A 10% citric acid solution was added, the mixture was stirred for 10 minutes, and then the liquid-liquid was separated and the aqueous layer was discarded. Celite (3.0 g) was charged into the organic layer, stirred at 0°C for 1 hour, and then filtered. The residue was washed with isopropyl acetate, and the filtrate and washings were combined. The combined solution was washed twice with 10% saline solution, and the solvent was replaced with acetonitrile to obtain an acetonitrile solution of compound 8 (73.5 g). The yield was assumed to be 100% and used in the next step.

[0296] Example 52: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate (compound 11c) 1 / 3 of the acetonitrile solution of tert-butyl 2-[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]-6-[(1-{(2R)-2-[(triphenylmethyl)amino]-2-[1-(triphenylmethyl)-1H-imidazole-4-yl]acetyl}azetidine-3-yl)oxy]benzoate (compound 8), obtained in Example 51, was placed in a reaction vessel, and acetonitrile (41.0 g) was added. 85% phosphoric acid (46.7 g) was added dropwise under a nitrogen stream at a temperature below 20°C, and the dropping apparatus was washed with purified water (13.18 g) and the washings were also added. The reaction mixture was heated to 40°C, and after 6 hours, seed crystals were added, and the mixture was heated and stirred for an additional 18 hours. The reaction mixture was cooled to 20°C, and acetonitrile (63.4 g) was added dropwise. The mixture was stirred overnight at the same temperature, and a methylboronic acid methanol solution prepared from methylboronic acid (2.69 g) and methanol (24.1 g) was added dropwise, and the mixture was stirred overnight. The reaction mixture was filtered, and the resulting wet material was washed with a washing solution prepared by pre-mixing acetonitrile (11.9 g), methanol (2.42 g), 85% phosphoric acid (4.60 g), and purified water (1.32 g). The wet material was washed twice with a mixed solvent of acetonitrile and water, and four times with methanol (32.2 g), after which it was dried under reduced pressure. Compound 11c was obtained as pale pink crystals in a yield of 4.74 g with a content yield of 80.1%. The crystals were confirmed to be morphology III by XRD (Figure 22).

[0297] Example 53: Method for producing 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid (compound 11a and / or 11b) Wet crystals of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid phosphate, obtained by solid-liquid separation and washing in the same manner as in Example 18, were dried under various conditions and their XRD was measured. The results are shown in Table 20.

[0298]

[0299] Example 54: MicroED Crystal Structure Analysis of Morphology I 3D ED / MicroED measurements of Morphology I were performed using the "XtaLAB Synergy-ED" electron diffractometer from Rigaku Corporation and JEOL Ltd. This instrument is equipped with the ED software "CrysAlisPro for ED" and the "HyPix-ED" detector optimized for 3D ED / MicroED experimental configurations (Ito, S., CrystEngComm, 23:8622-8630, 2021). The dataset was collected at -150°C at a wavelength of 0.0251 Å corresponding to an acceleration voltage of 200 kV. The dose rate of the electron beam irradiating the crystal was approximately 0.01 e - / Å 2The time interval was set to / s. The sample was loaded onto a copper grid with a carbon film (TED PELLA INC., USA) by scooping a small amount of powder sample with the grid. Excess sample was removed by lightly tapping the tweezers holding the grid, and then the grid was set into a cryotransfer holder (Gatan, Inc., USA). All data acquisition processes, including the search for high-quality crystals, acquisition of diffraction patterns, intensity extraction, and determination of the primary space group, were performed using "CrysAlisPro for ED" (Rigaku Co., Ltd., Tokyo). During the measurement, the crystal was continuously rotated at 1° / second, and diffraction patterns were acquired every 0.15°. The tilt angle range was from -60° to 60°, for a total of 120°. Four datasets were integrated to enhance the completeness of the structure of this compound. The initial phase was determined by a direct method using "SHELXD" (Usona, I., Acta Crystallogr. D, 74:106-116, 2018), and the resulting structure was refined using the full matrix least squares method with "SHELXL" (Sheldrick, GM, Acta Crystallogr C,, 71:3-8, 2015) on the "Olex2" (Dolomanov, O., J. Appl. Cryst., 42:339-341, 2009) single-crystal structure analysis platform. The structure was kinematically refined, and dynamic effects in electron diffraction were not considered. In the measurement, the molar ratio of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaporinine-8-carboxylic acid, phosphoric acid, and water was 2:5:4. As a result, it was confirmed that form I is a 2.5-phosphate dihydrate. The crystal structure of form I, analyzed by MicroED, is shown in Figure 48. Furthermore, for ease of understanding, the chemical structural formulas representing the constituent components of the crystal based on the crystal structure are shown in Figure 49.

[0300] Example 55: MicroED crystal structure analysis of Morphology II. 3D ED / MicroED measurements of Morphology II were performed using the "XtaLAB Synergy-ED" electron diffraction instrument by Rigaku Corporation and JEOL Ltd. This instrument uses the "CrysAlis" ED software. Pro It is equipped with the "for ED" and the "HyPix-ED" detector, which is optimized for 3D ED / MicroED experimental configurations. The dataset was collected at a wavelength of 0.0251 Å corresponding to an acceleration voltage of 200 kV. The dose rate of the electron beam irradiating the crystal was approximately 0.01 e - / Å 2 The setting was changed to / s. As a sample, a small amount of powder sample of morphology I was scooped up with a grid and placed on a copper grid with a carbon film (TED PELLA INC., USA). Excess sample was removed by lightly tapping the tweezers holding the grid, and then the grid was set in a cryotransfer holder (Gatan, Inc., USA). The crystals of morphology I were transferred under ultra-high vacuum (vacuum degree (10 -5 The samples were held at Pa for 16 hours, converted to morphology II in situ, and measured at -174°C. All data acquisition processes, including the search for high-quality crystals, acquisition of diffraction patterns, intensity extraction, and determination of the primary space group, were performed using "CrysAlis". ProThe analysis was performed using "for ED" (Rigaku Co., Ltd., Tokyo). During the measurement, the crystal was continuously rotated at 1° / second, and diffraction patterns were acquired every 0.15°. The tilt angle range was from -60° to 60°, for a total of 120°. To improve the structural refinement of this compound, three datasets were integrated. The initial phase was determined by the direct method using "SHELXD," and the obtained structure was refined using the full matrix least squares method with "SHELXL" on the "Olex2" single crystal structure analysis platform. The structure was kinematically refined, and the dynamic effects in electron diffraction were not considered. In this measurement, the molar ratio of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid, phosphoric acid, and water was 2:5:0. As a result, it was confirmed that form II is a 2,5-phosphate anhydride. The crystal structure of form II, analyzed by MicroED, is shown in Figure 50 (two molecules of compound 20 are overlapping, so only one molecule is shown). Furthermore, for ease of understanding, the chemical structural formulas representing the constituent components of the crystal based on the crystal structure are shown in Figure 51.

[0301] Example 56: MicroED crystal structure analysis of Morphology III. 3D ED / MicroED measurements of Morphology III were performed using the "XtaLAB Synergy-ED" electron diffraction instrument from Rigaku Corporation and JEOL Ltd. This instrument uses the "CrysAlis" ED software. Pro It is equipped with the "for ED" and the "HyPix-ED" detector, which is optimized for 3D ED / MicroED experimental configurations. The dataset was collected at a wavelength of 0.0251 Å corresponding to an acceleration voltage of 200 kV at -160°C. The dose rate of the electron beam irradiating the crystal was approximately 0.01 e - / Å 2The time was set to / s. The sample was loaded onto a carbon-film coated copper grid (TED PELLA INC., USA) by scooping up a small amount of powder sample with a grid. Excess sample was removed by lightly tapping the tweezers holding the grid, and then the grid was set into a cryotransfer holder (Gatan, Inc., USA). All data acquisition processes, including the search for high-quality crystals, acquisition of diffraction patterns, intensity extraction, and determination of the primary space group, were performed using "CrysAlis". Pro The analysis was performed using "for ED" (Rigaku Co., Ltd., Tokyo). During the measurement, the crystal was continuously rotated at 1° / second, and diffraction patterns were acquired every 0.15°. The tilt angle range was from -60° to 60°, for a total of 120°. To improve the structural refinement of this compound, two datasets were integrated. The initial phase was determined by the direct method using "SHELXD," and the obtained structure was refined using the full matrix least squares method with "SHELXL" on the "Olex2" single crystal structure analysis platform. The structure was kinematically refined, and the dynamic effects in electron diffraction were not considered. In this measurement, the molar ratio of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid, phosphoric acid, and water was 2:6:0. As a result, it was confirmed that form III is a 3.0-phosphate anhydride. The crystal structure of form III, analyzed by MicroED, is shown in Figure 52. Furthermore, for ease of understanding, the chemical structural formulas representing the constituent components of the crystal based on the crystal structure are shown in Figure 53.

[0302] Example 57: MicroED Crystal Structure Analysis of Morphology VIII 3D ED / MicroED measurements of morphology VIII were performed using the field emission cryo-electron microscope "CRYO ARM 200 (JEOL Ltd.)" at the Research Center for Sustainable Humanodynamics, University of Tsukuba. This instrument is equipped with the ED software "Serial EM" and the "Rio 16M (Gatan)" detector optimized for 3D ED / MicroED experimental configurations. The dataset was collected at 92 K with a wavelength of 0.0251 Å corresponding to an acceleration voltage of 200 kV. The dose rate of the electron beam irradiating the crystal was approximately 0.05 e - / Å 2The time interval was set to / s. The sample was placed on QUANTIFOIL Holey Carbon support film grids (Quantifoil, Cu, 300mesh, R1.2 / 1.3) that had been hydrophilized using the hydrophilization treatment device "PIB-10" by lightly rubbing the grid onto a small amount of powder sample on a glass slide. Excess sample was removed by lightly tapping the tweezers holding the grid, and then the grid was pre-cooled with liquid nitrogen before being introduced into the electron microscope. All operations, including the search for high-quality crystals, acquisition of diffraction patterns, extraction of intensity, and determination of the primary space group, were performed using "Serial EM". During the measurement, the crystal was continuously rotated at 1° / second, and diffraction patterns were acquired at 1° intervals. The tilt angle range was from -65° to 65°, totaling 130°. To refine the structure of this compound, 114 datasets were integrated to improve completeness. The initial phase was determined by specifying the space group as P21 using "SHELXD," and the obtained structure was refined using the all-matrix least squares method with "SHELXL." The structure was kinematically refined, and dynamic effects in electron diffraction were not considered. The molar ratio of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxabolinine-8-carboxylic acid, phosphoric acid, hydrochloric acid, and water in this measurement was 1:2:1:1. As a result, it was confirmed that morphology VIII is 2.0-phosphate monohydrochloride monohydrate. The crystal structure of morphology VIII analyzed by MicroED is shown in Figure 54. Furthermore, for ease of understanding, the chemical structural formulas representing the constituent components of the crystal based on the crystal structure are shown in Figure 55.

[0303] (Note) As described above, the Disclosure has been illustrated using preferred embodiments thereof, but it should be understood that the scope of the Disclosure should be interpreted solely by the claims. This Application claims priority over Japanese Patent Application No. 2024-221196 (filed December 17, 2024), the contents of which are incorporated herein by reference in their entirety. It should be understood that any patents, applications and other documents cited herein should be incorporated herein by reference in the same way that their contents are specifically described herein.

[0304] This disclosure makes it possible to provide phosphate, malonate, D-tartrate, phosphate D-tartrate, and hydrochloride phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid (a compound represented by formula (12a) described below) as crystals. These salts and their crystals have excellent β-lactamase inhibitory activity and are useful as prophylactic or therapeutic agents for bacterial infections, either in combination with β-lactam drugs or as monotherapy. Furthermore, the crystal form I of the phosphate of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid exhibits high thermal and hygroscopic stability, making it useful as a pharmaceutical product.

Claims

A pharmaceutically acceptable salt of 7-({1-[(2R)-2-amino-2-(1H-imidazole-4-yl)acetyl]azetidine-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxavorinine-8-carboxylic acid, wherein the pharmaceutically acceptable salt is selected from the group consisting of phosphate, malonate, D-tartrate, D-tartrate phosphate, and phosphate hydrochloride. 　 The salt according to claim 1, wherein the pharmaceutically acceptable salt is a phosphate salt. 　 The salt according to claim 2, wherein the phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 9.8 ± 0.2° and 12.5 ± 0.2°. 　 The salt according to claim 2, wherein the phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 9.8±0.2°, 12.5±0.2°, 12.6±0.2°, 14.2±0.2°, 14.6±0.2°, 16.0±0.2°, 20.0±0.2°, 20.2±0.2°, 20.4±0.2°, 21.2±0.2°, 22.6±0.2°, 23.5±0.2°, 24.1±0.2°, and 25.1±0.2°. 　 The salt according to claim 3 or claim 4, wherein the phosphate crystal is in form I. 　 The salt according to any one of claims 3 to 5, wherein the phosphate is crystalline, and the crystal exhibits a differential scanning calorimetry curve having an endothermic peak around 221°C. 　 The salt according to claim 2, wherein the phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 5.3 ± 0.2° and 10.6 ± 0.2°. 　 The salt according to claim 2, wherein the phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 5.3±0.2°, 10.6±0.2°, 13.5±0.2°, 15.6±0.2°, 18.1±0.2°, 18.6±0.2°, 20.1±0.2°, 21.6±0.2°, 24.1±0.2°, 25.8±0.2°, and 29.4±0.2°. 　 The salt according to claim 7 or claim 8, wherein the phosphate crystal is in form II. 　 The salt according to claim 2, wherein the phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 9.9 ± 0.2° and 16.5 ± 0.2°. 　 The salt according to claim 2, wherein the phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 9.9±0.2°, 15.4±0.2°, 16.5±0.2°, 20.2±0.2°, 20.6±0.2°, 21.2±0.2°, 22.0±0.2°, 22.9±0.2°, 23.8±0.2°, 24.3±0.2°, and 24.6±0.2°. 　 The salt according to claim 10 or claim 11, wherein the phosphate crystal is of form III. 　 The salt according to claim 1, wherein the pharmaceutically acceptable salt is a malonate. 　 The salt according to claim 13, wherein the malonate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 11.7 ± 0.2° and 12.3 ± 0.2°. 　 The salt according to claim 13, wherein the malonate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 6.3±0.2°, 11.7±0.2°, 12.3±0.2°, 16.6±0.2°, 20.5±0.2°, 21.3±0.2°, 21.9±0.2°, 22.2±0.2°, 22.8±0.2°, 23.4±0.2°, 25.1±0.2°, and 27.6±0.2°. 　 The salt according to claim 14 or claim 15, wherein the malonate crystal is morphology IV. 　 The salt according to claim 13, wherein the malonate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 10.8 ± 0.2° and 21.7 ± 0.2°. 　 The salt according to claim 13, wherein the malonate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 8.9±0.2°, 10.8±0.2°, 14.7±0.2°, 15.3±0.2°, 17.0±0.2°, 18.2±0.2°, 21.7±0.2°, 23.0±0.2°, 24.2±0.2°, 25.4±0.2°, 28.4±0.2°, and 28.7±0.2°. 　 The salt according to claim 17 or claim 18, wherein the malonate crystals are in form V. 　 The salt according to claim 1, wherein the pharmaceutically acceptable salt is D-tartrate. 　 The salt according to claim 20, wherein the D-tartrate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 12.7 ± 0.2° and 16.5 ± 0.2°. 　 The salt according to claim 20, wherein the D-tartrate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 10.4±0.2°, 11.8±0.2°, 12.2±0.2°, 12.7±0.2°, 14.6±0.2°, 15.6±0.2°, 16.5±0.2°, 21.1±0.2°, 21.8±0.2°, 22.9±0.2°, 23.5±0.2°, 24.7±0.2°, and 26.6±0.2°. 　 The salt according to claim 21 or claim 22, wherein the D-tartrate crystal is morphological VI. 　 The salt according to claim 1, wherein the pharmaceutically acceptable salt is D-tartrate phosphate. 　 The salt according to claim 24, wherein the D-tartrate phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 9.6 ± 0.2° and 23.6 ± 0.2°. 　 The salt according to claim 24, wherein the D-tartrate phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 9.6±0.2°, 13.3±0.2°, 17.1±0.2°, 19.8±0.2°, 21.4±0.2°, 22.0±0.2°, 23.6±0.2°, 25.2±0.2°, 26.4±0.2°, 27.4±0.2°, and 28.4±0.2°. 　 The salt according to claim 25 or claim 26, wherein the crystals of the D-tartrate phosphate are in form VII. 　 The salt according to claim 1, wherein the pharmaceutically acceptable salt is hydrochloric acid phosphate. 　 The salt according to claim 28, wherein the hydrochloric acid phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles (2θ) of 10.4 ± 0.2° and 25.9 ± 0.2°. 　 The salt according to claim 28, wherein the hydrochloric acid phosphate is crystalline, and the crystal exhibits an X-ray powder diffraction pattern having characteristic peaks at at least four diffraction angles (2θ) selected from 10.4±0.2°, 14.2±0.2°, 15.5±0.2°, 18.2±0.2°, 19.0±0.2°, 20.7±0.2°, 21.8±0.2°, 22.7±0.2°, 25.2±0.2°, 25.9±0.2°, 27.4±0.2°, 28.3±0.2°, 31.1±0.2°, and 31.6±0.2°. 　 The salt according to claim 29 or claim 30, wherein the hydrochloric acid phosphate crystals are of form VIII. 　 A pharmaceutical product containing the salt described in any one of claims 1 to 31 as an active ingredient. 　 The pharmaceutical product according to claim 32, which is a therapeutic or preventive agent for bacterial infections. 　 The pharmaceutical product according to claim 33, wherein the bacterial infection is a bacterial infection involving bacteria that may possess β-lactamase. 　 The pharmaceutical product according to claim 33 or claim 34, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory disease, pharyngitis / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphangitis / lymphadenitis, secondary infection of trauma / burns and surgical wounds, urinary tract infection, genital infection, eye infection, dental infection, complicated urinary tract infection, complicated intra-abdominal infection, hospital-acquired pneumonia, or ventilator-associated pneumonia. 　 A pharmaceutical composition comprising the salt described in any one of claims 1 to 31 and a pharmaceutically acceptable carrier. 　 The pharmaceutical composition according to claim 36, further comprising an additional agent. The pharmaceutical composition according to claim 37, wherein the additional agent is selected from the group consisting of antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, and anti-allergic agents. 　 The pharmaceutical composition according to claim 37 or claim 38, wherein the additional agent is a β-lactam drug. 　 The pharmaceutical composition according to claim 39, wherein the β-lactam drug is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem. 　 The pharmaceutical composition according to claim 36, comprising an additional agent. 　 The pharmaceutical composition according to claim 41, wherein the additional agent is selected from the group consisting of antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, and anti-allergic agents. 　 The pharmaceutical composition according to claim 41 or claim 42, wherein the additional agent is a β-lactam drug. 　 The pharmaceutical composition according to claim 43, wherein the β-lactam drug is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem. 　 A salt according to any one of claims 1 to 31 for treating a bacterial infection. 　 The salt according to claim 45, wherein the bacterial infection is a bacterial infection involving bacteria that may possess β-lactamase. 　 The salt according to claim 45 or claim 46, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory disease, pharyngitis / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphangitis / lymphadenitis, secondary infection of trauma / burns and surgical wounds, urinary tract infection, genital infection, eye infection, dental infection, complicated urinary tract infection, complicated intra-abdominal infection, hospital-acquired pneumonia, or ventilator-associated pneumonia. 　 A method for treating a bacterial infection, characterized by administering a therapeutically effective amount of the salt described in any one of claims 1 to 31 to a patient in need of treatment. 　 The method according to claim 48, wherein the bacterial infection is a bacterial infection involving bacteria that may possess β-lactamase. 　 The method according to claim 48 or claim 49, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory disease, pharyngitis / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphangitis / lymphadenitis, secondary infection of trauma / burns and surgical wounds, urinary tract infection, genital infection, eye infection, dental infection, complicated urinary tract infection, complicated intra-abdominal infection, hospital-acquired pneumonia, or ventilator-associated pneumonia. 　 The method according to any one of claims 48 to 50, characterized in that it is administered together with an additional drug. 　 The method according to claim 51, wherein the additional agent is selected from the group consisting of antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, and antiallergic agents. 　 The method according to claim 51 or claim 52, wherein the additional agent is a β-lactam drug. 　 The method according to claim 53, wherein the β-lactam drug is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem. 　 The following Step 7 is included: Equation (11a) Method for producing the compound represented by: Step 7 Equation (7) Compound represented by the formula [wherein PG ２ and PG ３ These are, independently, protecting groups of boronic acid. Equation (D) An amino acid derivative represented by the formula, or a salt thereof [wherein PG ４ and PG ５ These are, independently, protecting groups for amino groups. By subjecting them to a condensation reaction with ], Equation (8) Compound represented by the formula [wherein PG ２ PG ３ PG ４ and PG ５ This is synonymous with the above. The process of manufacturing [ ]. 　 The manufacturing method according to claim 55, wherein the reaction in Step 7 is carried out in a solvent selected from an amide solvent, an aromatic hydrocarbon solvent, a nitrile solvent, an ether solvent, and an ester solvent. 　 The manufacturing method according to claim 55 or claim 56, wherein the reaction in Step 7 is carried out in a temperature range of approximately -5°C to approximately 40°C. 　 The method for producing a product according to any one of claims 55 to 57, wherein the reaction in Step 7 is carried out in the presence of a coupling agent selected from O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), (hydroxyimino) ethyl cyanoethyl (Oxima), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), N,N-carbonyldimidazole (CDI), 1H-benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), and propylphosphonic anhydride (T3P). 　 The manufacturing method according to any one of claims 55 to 58, further comprising Step 8 below: Step 8 Equation (8) The compound represented by [wherein, PG ２ , PG ３ , PG ４ and PG ５ are as defined above.] is subjected to a deprotection reaction of the amino group, whereby Equation (9) A compound represented by the formula, or a salt thereof [wherein PG ２ PG ３ and PG ４ This is synonymous with the above. The process of manufacturing [ ]. 　 The manufacturing method according to any one of claims 55 to 59, further comprising Step 9 below: Step 9 Equation (9) A compound represented by the formula, or a salt thereof [wherein PG ２ PG ３ and PG ４ This is equivalent to the above. ] is given by formula (L) Tartaric acid derivative represented by the formula [wherein R is C １－３ Alkyl or C １－３ It is an alkoxy group. By subjecting it to salt formation with ], Equation (10) Compound represented by the formula [wherein PG ２ PG ３ PG ４ And R are the same as above. The process of manufacturing ]. 　 The manufacturing method according to any one of claims 55 to 60, further comprising Step 10 below: Step 10 Equation (10) Compound represented by the formula [wherein PG ２ PG ３ PG ４ And R is the same as above. By treating ] with phosphoric acid, Equation (11c) A process for producing the compound represented by the symbol. 　 The manufacturing method according to claim 61, wherein in the reaction of Step 10, phosphoric acid is used in an amount of about 20 to about 60 equivalents relative to the compound represented by formula (10). 　 The manufacturing method according to claim 61 or claim 62, wherein the reaction in Step 10 is carried out in a solvent containing a nitrile solvent. 　 The manufacturing method according to any one of claims 61 to 63, wherein a boronic acid derivative is added to the system after the reaction in Step 10 is completed. 　 A method for producing a compound represented by formula (11c) according to any one of claims 64, wherein a boronic acid derivative is added to the system, and then the compound represented by formula (11c) is crystallized in an acetonitrile-methanol-water system. 　 The manufacturing method according to any one of claims 61 to 65, wherein the compound represented by formula (11c) is obtained by solid-liquid separation, and then washed with a washing solution containing acetonitrile, methanol, phosphoric acid, and water. 　 The manufacturing method according to any one of claims 55 to 58, further comprising Step 11 below: Step 11 Equation (8) Compound represented by the formula [wherein PG ２ PG ３ PG ４ and PG ５ This is synonymous with the above. By treating ] with phosphoric acid, Equation (11c) A process for producing the compound represented by the symbol. 　 The manufacturing method according to claim 67, wherein in the reaction of Step 11, phosphoric acid is used in an amount of about 20 to about 60 equivalents relative to the compound represented by formula (8). 　 The manufacturing method according to claim 67 or claim 68, wherein the reaction in Step 11 is carried out in a solvent containing a nitrile solvent. 　 The manufacturing method according to any one of claims 67 to 69, wherein a boronic acid derivative is added to the system after the reaction in Step 11 is completed. 　 The method for producing a compound represented by formula (11c) according to claim 70, wherein a boronic acid derivative is added to the system, and then the compound represented by formula (11c) is crystallized in an acetonitrile-methanol-water system. 　 The manufacturing method according to any one of claims 67 to 71, wherein the compound represented by formula (11c) is obtained by solid-liquid separation, and then washed with a washing solution containing acetonitrile, methanol, phosphoric acid, and water. 　 The manufacturing method according to any one of claims 55 to 72, further comprising Step 12 below: Step 12 Equation (11c) Compounds represented by (i) Treatment with phosphoric acid in water or an inert solvent containing water, (ii) Treat with an inert solvent containing water. By any of the following methods Equation (11a) Compounds represented by and / or Equation (11b) A process for producing the compound represented by the symbol. 　 The manufacturing method according to claim 73, wherein in the method of reaction (i) of Step 12 described above, phosphoric acid is used in an amount of about 10 to about 40 equivalents relative to the compound represented by formula (11c). 　 The manufacturing method according to any one of claims 55 to 74, further comprising Step 13 below: Step 13 Equation (11b) By adjusting the humidity of the compound represented by, Equation (11a) A process of converting to a compound represented by the formula. 　 The manufacturing method according to claim 75, wherein the humidity control in Step 13 is performed under conditions of approximately 50 RH or higher. 　 The manufacturing method according to any one of claims 55 to 76, further comprising Step 1 below: Step 1 Equation (1) By subjecting a compound represented by [wherein X is a halogen atom], or a salt thereof [wherein X is a halogen atom], to a Boc(tert-butoxycarbonyl) reaction of two hydroxyl groups and a t-Bu(tert-butyl) esterification reaction of a carboxyl group, Equation (2) A process for producing a compound represented by [wherein X is the same as above]. 　 The manufacturing method according to any one of claims 55 to 77, further comprising Step 2 below: Step 2 Equation (2) By subjecting the compound represented by [wherein X is as defined above] to a selective deprotection reaction of the hydroxyl group at the 6th position, Equation (3) A process for producing a compound represented by [wherein X is the same as above]. 　 The manufacturing method according to any one of claims 55 to 78, further comprising Step 3 below: Step 3 Equation (3) A compound represented by formula (K) [wherein X is the same as above] is given by formula (K) Azetidine-3-ol represented by the formula [wherein PG] is an NH group protected azetidine-3-ol. １ It is a protecting group for amino groups. By subjecting it to the Mitsunobu reaction with ], Equation (4) A compound represented by the formula [wherein X and PG １ This is synonymous with the above. The process of manufacturing [ ]. 　 The manufacturing method according to any one of claims 55 to 79, further comprising Step 4 below: Step 4 Equation (4) A compound represented by the formula [wherein X and PG １ This is synonymous with the above. By subjecting ] to a vinylization reaction, Equation (5) Compound represented by the formula [wherein PG １ This is synonymous with the above. The process of manufacturing [ ]. 　 The manufacturing method according to any one of claims 55 to 80, further comprising Step 5 below: Step 5 Equation (5) Compound represented by the formula [wherein PG １ This is synonymous with the above. By subjecting ] to a hydroboration reaction, Equation (6) Compound represented by the formula [wherein PG １ PG ２ and PG ３ This is synonymous with the above. The process of manufacturing [ ]. 　 The manufacturing method according to any one of claims 55 to 81, further comprising Step 6 below: Step 6 Equation (6) Compound represented by the formula [wherein PG １ PG ２ and PG ３ This is synonymous with the above. By subjecting ] to a deprotection reaction of the azetidinyl group and converting it to a hydrochloride salt, Equation (7) Compound represented by the formula [wherein PG ２ and PG ３ This is synonymous with the above. The process of manufacturing [ ]. 　 Includes Step D below, Equation (D) An amino acid derivative represented by the formula, or a salt thereof [wherein PG ４ and PG ５ This is synonymous with the above. Method of manufacturing: StepD Formula (C) A step of producing an amino acid derivative represented by formula (D), or a salt thereof, by liberating a compound represented by and subjecting it to a protection reaction of the amino group and the imidazolyl group. 　 The manufacturing method according to claim 83, further comprising Steps B and C below: Step B Formula (B) By subjecting a compound represented by, or a salt thereof, to a ring-opening reaction, Formula (C') A process for producing a compound represented by or a salt thereof, and StepC By subjecting the compound represented by formula (C'), or a salt thereof, to salt formation with L-tartaric acid, Formula (C) A process for producing the compound represented by the symbol. PG １ The manufacturing method according to any one of claims 79 to 82, wherein the group is a benzyloxycarbonyl group. PG ２ and PG ３ The boronic acids protected by the following formulas independently represent (Ja), (Jb), (Jc), or (Jd): [In the formula, R １ and R ２ Each of them is independently C １－３ It is an alkyl group. A manufacturing method according to any one of claims 55 to 72, 81, 82, and 85, wherein the structure is represented by [the specified formula]. PG ２ and PG ３ The boronic acid protected by the following formulas independently (Je) or (Jf): A manufacturing method according to any one of claims 55 to 72, 81, 82, and 85, wherein the structure is represented by [the specified formula]. PG ４ and PG ５ However, each independently corresponds to the following equation (H) or (I): [In the formula, X ａ , X ｂ , X ｃ , X ｄ , X ｅ and X ｆ Each of these is independently a halogen atom or C １－３ It is an alkoxy group, m is an integer, either 0 or 1. A protecting group represented by the method according to any one of claims 55 to 72, 83, 84, 86, and 87. PG ４ and PG ５ However, each is independently represented by the formulas (Ha), (Hb), (Hc), or (Hd): A protecting group represented by the method according to any one of claims 55 to 72, 83, 84, 86, and 87. 　 The manufacturing method according to any one of claims 77 to 80, wherein X is a bromine atom. 　 The manufacturing method according to any one of claims 60 to 66, wherein R is a methyl group. 　 Formula (D) or (G): [In the formula, PG ４’ and PG ５’ These are independently expressed by the following formulas (H) or (I): [In the formula, X ａ , X ｂ , X ｃ , X ｄ , X ｅ and X ｆ Each of these is independently a halogen atom or C １－３ It is an alkoxy group, m is an integer, either 0 or 1. This is a protecting group represented by [this symbol]. An amino acid derivative represented by or a pharmaceutically acceptable salt thereof. PG ４’ and PG ５’ The compound according to claim 92 or a pharmaceutically acceptable salt thereof, wherein each of the protecting groups is independently represented by formula (H). The protecting group of formula (H) is one of the following formulas: (Ha), (Hb), (Hc), or (Hd): A protecting group represented by , the compound according to claim 92 or claim 93, or a pharmaceutically acceptable salt thereof. A compound represented by formula (20), or a pharmaceutically acceptable acid adduct thereof. A phosphate adduct or its hydrate obtained by adding 0.5 molecules of phosphoric acid to one molecule of the compound represented by formula (20). A phosphate adduct or its hydrate, obtained by adding one molecule of phosphate to one molecule of the compound represented by formula (20). A hydrochloric acid adduct or hydrate obtained by adding one molecule of hydrogen chloride to one molecule of the compound represented by formula (20).

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