RU2800050C2 - NEW β-LACTAMASE INHIBITOR AND A METHOD OF ITS PRODUCTION - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to intermediate compounds of formula (I), where A is Ra(Rb)N- or RcO-; B is NH; C is benzyl, H or SO₃M, where M is pyridinium or tetrabutylammonium; Ra and Rb are each, independently of each other, H, methyl, benzoyl, C_1-4 alkylcarbonyl, heterocyclylcarbonyl, where heterocyclyl is selected from tetrahydropyran, piperidine and pyrrolidine, and heteroarylcarbonyl, where heteroaryl is selected from furan, oxazole and pyridine; Rc is C_1-3 alkyl or 4–6-membered heterocyclyl having one nitrogen atom selected from azetidine, pyrrolidine and piperidine; A can be modified with 0 to 3 Fn1 substituents, where the Fn1 substituent that can modify A can be further modified with Fn1; Fn1 is C_1-6 alkyl which is selected from cyclopropylmethyl and cyclobutyl, O= or Rg-(CH₂)_0-1 — where Rg is a 4–7-membered heterocyclyl containing 1–2 heteroatoms selected from a nitrogen atom and an oxygen atom selected from azetidine, pyrrolidine, piperidine, morpholine, imizolidine, piperazine and diazepan, phenyl, a 5-membered heteroaryl having 1–2-nitrogen atoms, which is selected from pyrrole and imidazole, RdO₂S-, Re(Rf)N-, Re(Rf)NCO-, ReO-, ReOCO- or a protective group, where Rd is methyl; Re and Rf are each independently H or C_1-4 alkyl, and additionally Ra and Rb can be closed by bonding to give a 5–6 membered heterocyclyl having at least one nitrogen atom or nitrogen and oxygen, which is selected from pyrrolidine and morpholine, Rc and B can be closed by coupling to obtain a 5–6-membered heterocyclyl having a nitrogen atom and an oxygen atom, which is selected from oxazolidine and oxazinane, and Re and Rf can be closed by coupling with obtaining morpholine, the protective group is selected from tert-butoxycarbonyl, benzyloxycarbonyl and triisopropylsilyl, or pharmaceutically acceptable salts thereof. The invention also relates to intermediate compounds of formula (II), (IIa), (IIb) and (III), as well as to methods of their production.

EFFECT: invention provides methods of obtaining effective β-lactamase inhibitors and intermediate compounds for such inhibitors production for the treatment of bacterial infections.

13 cl, 5 dwg, 9 tbl, 122 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to a novel diazabicyclooctane derivative of formula (I), a pharmaceutically acceptable salt or solvate thereof. The present invention also relates to a method for its preparation and its use as a β-lactamase inhibitor for the treatment of bacterial infections. The present invention also relates to a pharmaceutical composition and a method for treating a bacterial infection using a compound of the present invention.

BACKGROUND OF THE INVENTION

Penicillins and cephalosporins are β-lactam antibiotics that are the most widely and frequently used in clinical medicine. However, the acquisition of resistance to β-lactam antibiotics by various pathogens has a significant negative effect on maintaining effective treatment of bacterial infections. The most significant known mechanism related to the acquisition of bacterial resistance is the formation of A, B and D classes of β-lactamases having a serine residue in the active site. These enzymes degrade β-lactam antibiotics, resulting in a loss of antimicrobial activity. Class A β-lactamases preferentially hydrolyze penicillins, and class C β-lactamases have a substrate profile favoring cephalosporins. Commercially available known β-lactamase inhibitors are clavulanic acid, sulbactam and tazobactam, and these inhibitors are effective primarily against bacteria producing the A class of β-lactamase and are used as a mixture with penicillin antibiotics. However, 250 or more types of β-lactamases have been described at present, and among them, in addition to the increase in class C β-lactamases, extended-spectrum β-lactamases (ESBLs) belonging to class A and D β-lactamases, other resistant bacteria that produce the KPC-2 class of β-lactamases degrading even carbapenem as a last possibility of β-lactam antibiotic are considered a problem. The development of a new inhibitor is highly desirable since commercially available inhibitors are not effective against such β-lactamases.

In addition, recently, infectious diseases caused by the above resistant bacteria as pathogenic bacteria have been found not only in severe infectious diseases, but also intermittently in community-acquired infectious diseases, so the development of a new inhibitor that can be used in combination with the first alternative drug (for example, penicillins or cephalosporins) in the city is urgently needed. However, although there are reports concerning potential inhibitors and reports concerning the treatment of severe infectious diseases, only a few candidates are being developed.

In recent years, US 7112592 (Patent Document 1), US 7612087 (Patent Document 2) and WO 2009/091856 (Patent Document 3) disclose that certain kinds of diazabicyclooctane derivatives are promising compounds for the treatment of infectious diseases as antibiotics having a β-lactam structure or not containing a β-lactamase inhibitor. As a method for their production, in addition to the methods mentioned in the documents cited above, the method described in WO 2010/126820 A2 (Patent Document 4) is known.

PRIOR ART DOCUMENTS

PATENT DOCUMENTS

Patent Document 1: US Patent No. 7112592

Patent Document 2: US Patent No. 7612087

Patent Document 3: WO 2009/091856 A2

Patent Document 4: WO 2010/126820 A2

DESCRIPTION OF THE INVENTION

PROBLEMS SOLVED BY THIS INVENTION

The currently available β-lactamase inhibitors are not sufficient to inhibit the ever-increasing β-lactamase, and new β-lactamase inhibitors are required for the difficult treatment of bacterial infections caused by resistant bacteria that produce class C β-lactamase, extended spectrum β-lactamase (ESBL) belonging to class A and D, or the KPC-2 β-lactamase class destroying even carbapenem as a last resort for a β-lactam antibiotic.

TROUBLESHOOTING TOOLS

The inventors of the present invention conducted research on a new β-lactamase inhibitor effective against β-lactamase-producing bacteria which currently cause the above problems, especially β-lactamase class A, class C and class D, and as a result, a new diazabicyclooctane derivative represented by formula (I) was found. It has also been found that the compound of the present invention significantly restores the antimicrobial effect of the β-lactam antibiotic combination against resistant bacteria when used in combination with the β-lactam antibiotic.

The method of the compound of formula c (II) which is included in formula (I) in accordance with this invention has also been determined:

in the above formulas (I) and (II) A is Ra(Rb)N- or RcO-; B is NH or NC _1-6 alkyl; C is benzyl, H or SO ₃ M, where M is H, an inorganic cation or an organic cation; Ra and Rb are each, independently of one another, H, C _1-6 alkyl or acyl; Rc is C _1-6 alkyl or heterocyclyl; A may be modified with 0 to 4 Fn1 substituents, where the Fn1 substituent may be further substituted; Fn1 is C _1-6 alkyl, O= or Rg-(CH ₂ ) _0-3- , where Rg is heterocyclyl, phenyl, heteroaryl, acyl, RdO ₂ S-, Re(Rf)N-, Re(Rf)NCO-, ReO-, ReOCO- or a protecting group, where Rd is C _1-6 alkyl or MO-; Re and Rf are each independently H or C _1-6 alkyl, and between Ra and Rb, between Rc and B, and between Re and Rf can be closed by bonding to give a heterocyclyl having at least one nitrogen atom.

Initially, in order to study the method for preparing the compound shown in (II) above, the method using the equivalent of phosgene and amine described in US Pat. to a compound represented by formula (IV-c):

in the above formula (IV-c), B and Rc are the same as those defined for the compound of formula (II) and OBn is benzyloxy,

the compound represented by the formula (IV-c) has N-alkoxycarbamoyl showing weak acidity in the side chain at position 2, so that the compound having the structure of diazabicyclooctane is represented by the formula (IIa):

in the above formula (IIa), Rc and B are the same as defined for the compound of formula (II) and OBn is benzyloxy,

can only be obtained with a very small yield.

Also, the method described in WO 2009/133442 A1 or WO 2010/126820 A2 introduces a side chain at position 2 at the initial stage of the production process, which is not cheap, and therefore the method is not necessarily interesting for a commercial production process, and it is desirable to develop a production method that can be easily transferred to an industrial scale.

Therefore, the present inventors have found compounds represented by the following formula (IV-a2), (IV-a3) or (IV-a4):

in the above formulas (IV-a2), (IV-a3) or (IV-a4), TFA is trifluoroacetyl, Boc is t-butoxycarbonyl, Teos is 2-trimethylsilylethoxycarbonyl, and OBn is benzyloxy,

as more useful starting materials and constantly studied them in order to bring them to the compounds of the above formula (IV-c) and the above formula (IIa).

As a result, a method for producing a compound represented by formula (III) was obtained.

in the above formula (III) Rc, B and M have the same meanings as defined for the compound of the above formula (II),

which is included in the compound of the above formula (II).

That is, the present invention relates to

(1) the diazabicyclooctane derivative represented by the formula (I),

In the above formula (I), A is Ra(Rb)N- or RCO-; B is NH or NC _1-6 alkyl; C is benzyl, H or SO ₃ M, where M is H, an inorganic cation or an organic cation; Ra and Rb are each, independently of one another, H, C _1-6 alkyl or acyl; Rc is C _1-6 alkyl or heterocyclyl; A may be modified with 0 to 4 Fn1 substituents, where the Fn1 substituent may be further substituted; Fn1 is C _1-6 alkyl, O= or Rg-(CH ₂ ) _0-3- , where Rg is heterocyclyl, phenyl, heteroaryl, acyl, RdO ₂ S-, Re(Rf)N-, Re(Rf)NCO-, ReO-, ReOCO- or a protecting group, where Rd is C _1-6 alkyl or MO-; Re and Rf are each independently H or C _1-6 alkyl, and between Ra and Rb, between Rc and B, and between Re and Rf can be closed by coupling to give a heterocyclyl having at least one nitrogen atom, a pharmaceutically acceptable salt or solvate thereof.

Also, in accordance with another aspect of the present invention, it relates to

(2) a diazabicyclooctane derivative represented by the following formula (II):

In the above formula (II), Rc is C _1-6 alkyl or heterocyclyl; B is NH or NC _1-6 alkyl; C is benzyl, H or SO ₃ M, where M is H, an inorganic cation or an organic cation; Rc may be modified with 0 to 4 Fn1 substituents, where the Fn1 substituent may be further substituted; Fn1 is C _1-6 alkyl, O= or Rg-(CH ₂ ) _0-3- , where Rg is heterocyclyl, phenyl, heteroaryl, acyl, RdO ₂ S-, Re(Rf)N-, Re(Rf)NCO-, ReO-, ReOCO- or a protecting group, where Rd is C _1-6 alkyl or MO-; Re and Rf are each independently H or C _1-6 alkyl, and between Rc and B, and between Re and Rf can be closed by bonding to give a heterocyclyl having at least one nitrogen atom,

its pharmaceutically acceptable salt or solvate.

Also, in accordance with another aspect of the present invention, it relates to

(3) a new diazabicyclooctane derivative represented by the following formula (IIa):

In the above formula (IIa), OBn is benzyloxy and Rc and B have the same meanings as defined for the compound of the above formula (II), its pharmaceutically acceptable salt or solvate, which is included in the above formula (II).

Also, in accordance with another aspect of the present invention, it relates to

(4) a diazabicyclooctane derivative represented by the following formula (IIb),

In the above formula (IIb), Rc and B have the same meanings as defined for the compound of the above formula (II), its pharmaceutically acceptable salt or solvate, which is included in the above formula (II).

Also, in accordance with another aspect of the present invention, it relates to

(5) a diazabicyclooctane derivative represented by the following formula (III):

in the above formula (III), Rc, B and M have the same meanings as defined for the compound of the above formula (II), its pharmaceutically acceptable salt or solvate.

Also, in accordance with another aspect of the present invention, it relates to

(6) the compound according to any of the above (1) to (5) which is represented by one of the following formulas:

in the formulas above, P ² is t-butoxycarbonyl (Boc), benzyloxycarbonyl or (Cbz) or H; P ³ is benzyl (Bn), H or SO ₃ M; where M is H, sodium, pyridinium or tetrabutylammonium,

its pharmaceutically acceptable salt or solvate.

Another aspect of the present invention relates to

(7) the compound according to any of the above items (1) - (3), which includes

(2S,5R)-N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(methylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-N-[2-(propan-2-ylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-{[(2S)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-{[(2R)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-(3-aminopropoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[(2S)-azetidin-2-ylmethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-N-[(2R)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-N-[(2S)-piperidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, or

(2S,5R)-N-(azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

a pharmaceutically acceptable salt or solvate thereof.

Also, according to another aspect of the present invention, it relates to (8) a pharmaceutical composition comprising a diazabicyclooctane derivative represented by the above formula (I), a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable carrier.

In addition, according to another aspect of the present invention, it relates to (9) a pharmaceutical composition according to paragraph (8) for administration in combination with a β-lactam antibiotic.

Moreover, according to another aspect of the present invention, it relates to (10) the pharmaceutical composition of (8) or (9) for treating a bacterial infection.

In addition, according to another aspect of the present invention, it relates to (11) a β-lactamase inhibitor containing a diazabicyclooctane derivative represented by the above formula (I), a pharmaceutically acceptable salt or solvate thereof.

According to another aspect of the present invention, it relates to (12) a pharmaceutical composition containing the above β-lactamase inhibitor, β-lactam antibiotic and, optionally, a pharmaceutically acceptable carrier.

In addition, according to another aspect of the present invention, it relates to (13) a pharmaceutical composition containing the above β-lactamase inhibitor, β-lactam antibiotic selected from the group consisting of ampicillin, amoxicillin, piperacillin, ticarcillin, flomoxef, cefotaxime, ceftriaxone, ceftazidime, cefepime, ceftaroline, ceftolosan, imipenem, meropenem, biapenem, doripenem, ertapenem and aztreonam, and optionally a pharmaceutically acceptable carrier.

In addition, according to another aspect of the present invention, there is provided a method for treating bacterial infections, and (14) a method for treating a bacterial infection, which comprises administering the above β-lactamase inhibitor and a β-lactam antibiotic in combination.

In addition, according to another aspect of the present invention, a method for treating bacterial infections is provided, and (15) a method for treating a bacterial infection is provided, which comprises administering a β-lactamase inhibitor and a β-lactam antibiotic selected from the group consisting of ampicillin, amoxicillin, piperacillin, ticarcillin, flomoxef, cefotaxime, ceftriaxone, ceftazidime, cefepime, ceftaro lin, ceftolosan, imipenem, meropenem, biapenem, doripenem, ertapenem and aztreonam, in combination.

In addition, according to another aspect of the present invention, there is provided a method for treating bacterial infections and a method for treating a single or mixed bacterial infection caused by at least one of Escherichia coli, Klebsiella pneumoniae, Enterobacter croacare, Citrobacter freundii, Serratia marcescens, Morganella morganii, Pseudomonas aeruginosa and Acinetobacter baumannii, which comprises administering a β-lact inhibitor ointment and a β-lactam antibiotic selected from the group consisting of ampicillin, amoxicillin, piperacillin, ticarcillin, flomoxef, cefotaxime, ceftriaxone, ceftazidime, cefepime, ceftaroline, ceftolosan, imipenem, meropenem, biapenem, doripenem, ertapenem and aztreonam, in combination.

In addition, according to another aspect of the present invention, it relates to a method for producing a compound represented by the following formula (III):

in the above formula (III) Rc, B and M have the same meanings as defined for the compound of the above formula (II),

which is included in the above formula (II), which includes (16) a combination of the compound represented by the following formula (IV-a):

in the above formula (IV-a), P ¹ is a protective group that can be removed with an acid, a base, or a nucleophilic agent; and OBn is benzyloxy,

with an RcOBH compound using an active ester, an active amide, or a dehydrating condensing agent to obtain a compound represented by the following formula (IV-b):

in the above formula (IV-b), P ¹ is a protective group that can be removed with an acid, a base, or a nucleophilic agent; Rc and B are as defined for formula (II) above, and OBn is benzyloxy,

deprotection of P ¹ , which is a protecting group, to obtain a compound represented by the following formula (IV-c):

in the above formula (IV-c), Rc and B have the meanings defined for the above formula (II), and OBn is benzyloxy,

silylation of a compound in a reaction system, followed by subjecting an intramolecular urea formation reaction to obtain a compound represented by the following formula (IIa):

in the above formula (IIa), Rc and B have the meanings defined for the above formula (II), and OBn is benzyloxy,

then, removing the benzyl or benzyloxy at the 6-position using a hydrogenolysis catalyst under a hydrogen atmosphere to obtain a compound represented by the following formula (IIb):

in the above formula (IIb), Rc and B have the meanings defined for the above formula (II),

and sulfonation of the hydroxyl group at position 6 in the presence of a base and, if necessary, deprotection of the side chain: RcOB- to obtain a compound represented by the following formula (III).

In addition, according to another aspect of the present invention, it relates to a method for producing a compound represented by the following formula (IIa):

in the above formula (IIa), OBn is benzyloxy and Rc and B have the meanings defined for the above formula (II),

which is included in the above formula (II), which includes

(17) a combination of a compound represented by the following formula (IV-a):

in the above formula (IV-a), P ¹ is a protective group that can be removed with an acid, a base, or a nucleophilic agent; and OBn is benzyloxy,

with the compound: RcOBH using an active ester, an active amide or a dehydrating condensing agent to obtain a compound represented by the following formula (IV-b):

in the above formula (IV-b), P ¹ is a protective group that can be removed with an acid, a base, or a nucleophilic agent; Rc and B are as defined for formula (II) above, and OBn is benzyloxy,

deprotection of P ¹ , which is a protecting group, to obtain a compound represented by the following formula (IV-c):

in the above formula (IV-c), Rc and B have the meanings defined for the above formula (II), and OBn is benzyloxy,

silylation of the compound in the reaction system, followed by subjecting an intramolecular urea formation reaction to obtain a compound represented by the following formula (IIa).

In addition, according to another aspect of the present invention, it relates to a method for producing a compound represented by the following formula (IIa):

in the above formula (IIa), OBn is benzyloxy and Rc and B have the meanings defined for the above formula (II),

which is included in the above formula (II), which includes

(18) silylation represented by the following formula (IV-c):

in the above formula (IV-c), Rc and B have the meanings defined for the above formula (II), and OBn is benzyloxy,

in a reaction system, followed by an intramolecular urea formation reaction to obtain a compound represented by the following formula (IIa).

In addition, according to another aspect of the present invention, it relates to a method for producing a compound represented by the following formula (III):

in the above formula (III), Rc, B and M have the meanings defined for the above formula (II),

which is included in the above formula (II), which includes

(19) removal of benzyl or benzyloxy at the 6-position of the compound represented by the following formula (IIa):

in the above formula (IIa), Rc and B have the meanings defined for the above formula (II), and OBn is benzyloxy,

using a hydrogenolysis catalyst under a hydrogen atmosphere to obtain a compound represented by the following formula (IIb):

in the above formula (IIb), Rc and B have the meanings defined for the above formula (II),

and sulfonation of the hydroxyl group at position 6 in the presence of a base and, if necessary, deprotection of the side chain: RcOB- to obtain a compound represented by the following formula (III).

In addition, according to another aspect of the present invention, it relates to a method for producing (2S,5R)-N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide represented by the following formula (III-059):

which includes

(20) among the compounds represented by the following formulas (IV-a2), (IV-a3) and (IV-a4):

in the above formula (IV-a2), (IV-a3) or (IV-a4), TFA is trifluoroacetyl, Boc is t-butoxycarbonyl, Teos is 2-trimethylsilylethoxycarbonyl and OBn is benzyloxy,

a combination of a compound represented by formula (IV-a2) or (IV-a4) with tert-butyl 2-(aminooxy)ethyl carbamate using an active ester, an active amide or a dehydrating condensing agent, or

combining a compound represented by formula (IV-a3) with benzyl 2-(aminooxy)ethylcarbamate using an active ester, an active amide or a dehydrating condensing agent,

to obtain a compound represented by the following formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or (IV-b4-Boc-059):

in the above formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or (IV-b4-Boc-059), TFA is trifluoroacetyl, Boc is t-butoxycarbonyl, Cbz is benzyloxycarbonyl, Teos is 2-trimethylsilylethoxycarbonyl and OBn is benzyloxy,

removal of the trifluoroacetyl compound represented by the formula (IV-b2-Boc-059) by treatment with a base to obtain a compound represented by the following formula (IV-c-Boc-059):

in the above formula (IV-c-Boc-059), Boc is t-butoxycarbonyl, Cbz is benzyloxycarbonyl and OBn is benzyloxy,

removing tert-butoxycarbonyl of a compound represented by formula (IV-b3-CBZ-059) by treatment with acid to obtain a compound represented by the following formula (IV-c-Cbz-059), or

removing 2-trimethylsilylethoxycarbonyl of a compound represented by formula (IV-b4-Boc-059) with fluoride to obtain a compound represented by the following formula (IV-c-Boc-059),

then, after silylation of the above (IV-c-Boc-059) or (IV-c-Cbz-059) in the reaction system, an intramolecular urea formation reaction to obtain a compound represented by the following formula (IIa-Boc-059) or (IIa-Cbz-059):

in the above formula (IIa-Boc-059) or (IIa-Cbz-059) Boc is t-butoxycarbonyl, Cbz is benzyloxycarbonyl and OBn is benzyloxy,

removing benzyl from the benzyloxy at the 6-position of a compound represented by formula (IIa-Boc-059) using a hydrogenolysis catalyst under hydrogen atmosphere, or

removing the benzyl from the benzyloxy at the 6-position of the compound represented by the formula (IIa-Cbz-059) using a hydrogenolysis catalyst under hydrogen atmosphere, and simultaneously tert-butoxycarbonylating it in the presence of di-tert-butoxydicarbonate to obtain the compound represented by the following formula (IIb-Boc-059):

in the above formula (IIb-Boc-059), Boc is t-butoxycarbonyl,

sulfonation of the hydroxyl group at position 6 to obtain a compound represented by the following formula (III-Boc-059):

in the above formula (III-Boc-059), Boc is t-butoxycarbonyl and M is H, pyridinium, sodium or tetrabutylammonium,

and deprotection of the t-butoxycarbonyl by treatment with acid to obtain a compound represented by the following formula (III-059).

Furthermore, according to another aspect of the present invention, it relates to a process for the preparation of tert-butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octo-2-yl]carbonyl}amino)oxy]ethyl}carbamate or benzyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diaza bicyclo[3.2.1]octo-2-yl]carbonyl}amino)oxy]ethyl}carbamate represented by the following formulas (IIa-Boc-059) or (IIa-Cbz-059):

in the above formulas (IIa-Boc-059) or (IIa-Cbz-059), Boc is t-butoxycarbonyl, Cbz is benzyloxycarbonyl and OBn is benzyloxy,

which includes

(21) among the compounds represented by the following formulas (IV-a2), (IV-a3) and (IV-a4):

in the above formulas (IV-a2), (IV-a3) and (IV-a4), TFA is trifluoroacetyl, Boc is t-butoxycarbonyl, Teos is 2-trimethylsilylethoxycarbonyl and OBn is benzyloxy,

the combination of each of the compounds represented by formulas (IV-a2) and (IV-a4) using tert-butyl 2-(aminooxy)ethylcarbamate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole monohydrate in combination,

the combination of a compound represented by formula (IV-a3) using benzyl 2-(aminooxy)ethylcarbamate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole monohydrate in combination,

to obtain a compound represented by the above formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or (IV-b4-Boc-059):

in the above formulas (IV-b2-Boc-059), (IV-b3-Cbz-059) or (IV-b4-Boc-059), TFA is trifluoroacetyl, Boc is t-butoxycarbonyl, Cbz is benzyloxycarlonyl, Teos is 2-trimethylsilylethoxycarbonyl and OBn is benzyloxy,

removal of trifluoroacetyl from a compound represented by formula (IV-b2-Boc-059) using a base selected from lithium hydroxide, sodium hydroxide and potassium hydroxide to obtain a compound represented by the above formula (IV-c-Boc-059):

in the above formula (IV-c-Boc-059) Boc is t-butoxycarbonyl, Cbz is benzyloxycarlonyl, and OBn is benzyloxy,

removing tert-butoxycarbonyl from a compound represented by formula (IV-b3-Cbz-059) using an acid selected from hydrochloric acid, sulfuric acid, methanesulfonic acid and trifluoroacetic acid to obtain a compound represented by the above formula (IV-c-Cbz-059), or

removing 2-trimethylsilylethoxycarbonyl from the compound represented by the formula (IV-b4-Boc-059) using tetrabutylammonium fluoride to obtain the compound represented by the above formula (IV-c-Boc-059), and

silylation of a compound represented by formula (IV-b4-Boc-059) or (IV-c-Cbz-059) using chlorotrialkylsilane in a reaction system, followed by formation of an intramolecular urea using phosgene or diphosgene to obtain a compound represented by formula (IIa-Boc-059) or (IIa-Cbz-059).

According to another aspect of the present invention, it relates to a process for the preparation of tert-butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octo-2-yl]carbonyl}amino)oxy]ethyl}carbamate or benzyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[ 3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate represented by the following formula (IIa-Boc-059) or (IIa-Cbz-059):

in the above formula (IIa-Boc-059) or (IIa-Cbz-059) Boc is t-butoxycarbonyl, Cbz is benzyloxycarlonyl, and OBn is benzyloxy,

which includes

(22) silylation of a compound represented by the following formula (IV-c-Boc-059) or (IV-c-Cbz-059):

in the above formula (IV-c-Boc-059) or (IV-c-Cbz-059) Boc is t-butoxycarbonyl, Cbz is benzyloxycarlonyl, and OBn is benzyloxy,

using chlorotrimethylsilane in the reaction system, followed by the formation of intramolecular urea using phosgene or diphosgene to obtain a compound represented by formula (IIa-Boc-059) or (IIa-Cbz-059).

According to another aspect of the present invention, it relates to a process for the preparation of (2S,5R)-N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide represented by the following formula (III-059):

which includes

(23) among the compounds represented by the following formulas (IIa-Boc-059) and (IIa-Cbz-059):

in the above formula (IIa-Boc-059) and (IIa-Cbz-059), Boc is t-butoxycarbonyl, Cbz is benzyloxycarlonyl, and OBn is benzyloxy,

removal of benzyl from the benzyloxy at the 6-position of the compound represented by formula (IIa-Boc-059) using palladium on carbon under hydrogen atmosphere, or removal of benzyl from the benzyloxy at position 6 of the compound represented by formula (IIa-Cbz-059) using palladium on carbon under hydrogen atmosphere in the presence of di-tert-butoxydicarbonate, and simultaneous tert-butoxycarbonylation to obtain the compound represented by formula ( IIa-Sun-059):

in the above formula (IIb-Boc-059), Boc is t-butoxycarbonyl,

sulfonation of the hydroxyl group at position 6 using a sulfur trioxide-pyridine complex in the presence of pyridine, 2-picoline or 2,6-lutidine to give a compound represented by the formula (IIIb-Boc-059):

in the above formula (III-Boc-059), Boc is t-butoxycarbonyl and M is H, adidium, sodium or tetrabutylammonium,

and deprotection of t-butoxycarbonyl with an acid selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid and tetrafluoroboric acid to obtain a compound represented by formula (III-059).

In addition, according to another aspect of the present invention, it relates to a process for producing tert-butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate represented by the following formula (IIa-Boc-059):

in the above formula (IIa-Boc-059), Boc is t-butoxycarbonyl and OBn is benzyloxy,

which includes

(24) silylation of a compound represented by the following formula (IV-c-Boc-059):

in the above formula (IV-c-Boc-059), Boc is t-butoxycarbonyl and OBn is benzyloxy,

using triethylamine and chlorotrimethylsilane in a reaction system, followed by the formation of intramolecular urea using phosgene or diphosgene with a catalytic amount of 4-dimethylaminepyridine to obtain a compound represented by formula (IIa-Boc-059).

In addition, according to another aspect of the present invention, it relates to a method for producing (2S,5R)-N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide represented by the following formula (III-059):

which includes

(25) removal of benzyl from benzyloxy at the 6-position of the compound represented by the formula (IIa-Boc-059):

in the above formula (IIa-Boc-059) Boc is t-butoxycarbonyl and OBn is benzyloxy,

using palladium-on-charcoal under a hydrogen atmosphere to obtain a compound represented by the formula (IIb-Boc-059):

in the above formula (IIb-Boc-059), Boc is t-butoxycarbonyl,

sulfation of the hydroxyl group at position 6 using a sulfur trioxide-pyridine complex in the presence of pyridine, 2-picoline or 2,6-lutidine to obtain a compound represented by formula (III-Boc-059):

in the above formula (III-Boc-059), Boc is t-butoxycarbonyl and M is H, adidium, sodium or tetrabutylammonium,

and deprotection of t-butoxycarbonyl with an acid selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid and tetrafluoroboric acid to obtain a compound represented by formula (III-059).

In addition, according to another aspect of the present invention, it relates to a process for the preparation of (2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate or its hydrochloride, which comprises (26) subjecting the new (2S,5S)-5-hydroxypiperidine-2-carboxylic acid or its hydrochloride to methyl esterification, trifluoroacetylation, benzyloxyamination of the C5 hydroxyl group, and removal of trifluoroacetyl , where each step proceeds without purification, followed by crystallization as the hydrochloride, isolating and purifying (2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate or its hydrochloride.

Another aspect of the present invention relates to (27) compounds represented by the formulas:

in the above formula, TFA is trifluoroacetyl, OMe is methoxy, Boc is t-butoxycarbonyl, Teos is 2-trimethylsilylethoxycarbonyl, and OBn is benzyloxy.

EFFECTS OF THE INVENTION

The novel diazabicyclooctane derivatives represented by the above formula (I) provided in the present invention have a strong inhibitory effect against various kinds of β-lactamases. In particular, they have a strong inhibitory effect against class A, class C and class D β-lactamases. More specifically, they have a strong inhibitory effect against the C class of β-lactamase, extended spectrum β-lactamase (ESBL) and the KPC-2 class of β-lactamase, and the antimicrobial activity of the existing β-lactam antibiotic against bacteria producing these β-lactamase resistant to β-lactam antibiotic can be largely restored in combination with the compound of the present invention.

In addition, a method for producing a compound represented by the following formula (II):

in the above formula (II), Rc is C _1-6 alkyl or heterocyclyl; B is NH or NC _1-6 alkyl; C is benzyl, H or SO ₃ M, where M is H, an inorganic cation or an organic cation; Rc may be modified with 0 to 4 Fn1 substituents, where the Fn1 substituent may be further substituted; Fn1 is C _1-6 alkyl, O= or Rg-(CH ₂ ) _0-3- , where Rg is heterocyclyl, phenyl, heteroaryl, acyl, RdO ₂ S-, Re(Rf)N-, Re(Rf)NCO-, ReO-, ReOCO- or a protecting group, where Rd is C _1-6 alkyl or MO-; Re and Rf are each independently H or C _1-6 alkyl, and between Ra and Rb, between Rc and B, and between Re and Rf can be closed by bonding to give a heterocyclyl having at least one nitrogen atom,

which is included in the compound of formula (I) represented by this invention is a production method that can be very useful as a commercial production method.

BRIEF DESCRIPTION OF THE FIGURES

In FIG. 1 shows antibacterial activity against 5 strains of KPC-2 or 3 producing strains of K. pneumoniae.

In FIG. 2 shows antibacterial activity against 5 constitutively expressing AmpC strains, P. aeruginosa.

In FIG. 3 shows antibacterial activity against 5 strains of constitutive expression of AmpC, Enterobacteriaceae.

In FIG. 4 shows antibacterial activity against 5 strains of IMP type metallo-β-lactamase producing strains of Enterobacteriaceae.

In FIG. 5 shows antibacterial activity against 5 strains producing CTX-M-15 (ESBL), E. coli.

BEST MODE FOR CARRYING OUT THE INVENTION

As described above, the present invention provides a novel diazabicyclooctane derivative represented by the following formula (I), a pharmaceutically acceptable salt or solvate thereof, and a β-lactamase inhibitor comprising a compound of formula (I):

in the above formula (I), A is Ra(Rb)N- or RcO-; B is NH or NC _1-6 alkyl; C is benzyl, H or SO ₃ M, where M is H, an inorganic cation or an organic cation; Ra and Rb are each, independently of one another, H, C _1-6 alkyl or acyl; Rc is C _1-6 alkyl or heterocyclyl; A may be modified with 0 to 4 Fn1 substituents, where the Fn1 substituent may be further substituted; Fn1 is C _1-6 alkyl, O= or Rg-(CH ₂ ) _0-3- , where Rg is heterocyclyl, phenyl, heteroaryl, acyl, RdO ₂ S-, Re(Rf)N-, Re(Rf)NCO-, ReO-, ReOCO- or a protecting group, where Rd is C _1-6 alkyl or MO-; Re and Rf are each independently H or C _1-6 alkyl, and between Ra and Rb, between Rc and B, and between Re and Rf can be closed by bonding to give a heterocyclyl having at least one nitrogen atom.

Hereinafter, the new diazabicyclooctane derivative represented by the formula (I) according to the present invention and the production method thereof, the β-lactamase inhibitor, and the use of the compound according to the present invention for treating bacterial infection will be explained in more detail, but the present invention is not limited to the scope of the specific examples presented.

The term "salt" as used herein means a pharmaceutically acceptable salt, and includes a base addition salt including an inorganic base or an organic base, and an acid addition salt including an inorganic acid and an organic acid.

The term "inorganic cation" refers to an alkali metal or alkaline earth metal, etc., and the term "organic cation" refers to an ammonium salt derived from a mono- or tri-substituted amine and a quaternary ammonium salt derived from a tetra-substituted amine or a substituted heteroaromatic ring.

If "M" is H and the compound according to this invention has an amino group, cyclic amines or aromatic amines that can be protonated in the molecule, the amino group, cyclic amines or aromatic amines in the molecule behave like a protonated ammonium salt, and the compound can take the form of an internal salt, which is also considered part of the compound in accordance with this invention. Further, if "M" is an organic cation and is present in the molecule of the compound of this invention as a quaternary ammonium salt, it may also be in the form of an internal salt, which is also considered part of the compound of this invention.

The term "modified" means the substitution of H in A or the Fn1 substituent and binds to or the Fn1 substituent.

The phrases "A may be modified with 0 to 4 Fn1 substituents, where the Fn1 substituent may be further substituted" mean that Fn1 which modifies A-(Fn1) _0-4 , A-(Fn1)(Fn1) _0-3 , A-(Fn1) ₂ (Fn1) _0-2 and A-(Fn1) ₃ (Fn1) _0-1 , etc.

As specific examples of a "protecting group" there may be mentioned a trialkylsilyl and a carbamate-type protecting group, preferably triisopropylsilyl, t-butyldimethylsilyl, t-butoxycarbonyl or benzyloxycarbonyl, which is a protecting group for the amino group and hydroxyl group described in Protective Groups in Organic Synthesis (T. W. Greene et al., Wiley, New York (1999)).

The solvent contained in the "solvate" may be water, methanol, ethanol, isopropanol, acetone and methyl ethyl ketone, more preferably water.

The term "C _1-6 alkyl" means an alkyl group having 1 to 6 carbon atoms, which may be straight, branched or cyclic.

The term "acyl" means formyl, benzoyl, phenylacetyl, C _1-6 alkylcarbonyl, heterocyclylcarbonyl and heteroarylcarbonyl.

The term "heterocyclyl" means a 3-7 membered monocyclic saturated heterocyclic ring or a non-aromatic ring containing from 1 to 3 nitrogen atoms, oxygen atoms and/or sulfur atoms in total.

The term "heteroaryl" means a 5-6 membered monocyclic heteroaromatic ring having from 1 to 4 nitrogen atoms, oxygen atoms and/or sulfur atoms in total.

The terms "Ra(Rb)N-" and "Re(Rf)N-" mean an amino group substituted with Ra and Rb, or Re and Rf.

The term "RcO-" means hydroxy linked to Rc, i. e. alkoxy or heterocyclyloxy, and the term "ReO-" means oxy associated with Re, i. e. alkoxy or hydroxy.

The term "RdO ₂ S-" means a sulfonyl associated with Pd.

The term "Re(Rf)NCO-" means a carbonyl associated with Re(Rf)N-.

The term "ReOCO-" means a carbonyl associated with ReO-.

The term "O=" means an oxo group.

Specific examples of bases that form "base addition salts" may include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium acetate, potassium acetate, trisodium citrate, sodium dihydrogen citrate, tripotassium citrate, potassium dihydrogen citrate, ammonia, methylamine, ethylamine, dimethylamine, diethylamine, trimethyl min, triethylamine, N-methylmorpholine, ethanolamine and triethanolamine, etc., preferably sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, sodium acetate, trisodium citrate, sodium dihydrogen citrate and triethanolamine, etc.

Specific examples of acids that form "acid addition salts" include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfuric acid, semisulfuric acid, thiocyanic acid, acetic acid, butyric acid, propionic acid, cyclopentanepropionic acid, pivalic acid, heptanoic acid, hexanoic acid, 3-phenylpro pionic acid, undecanoic acid, lactic acid, oxalic acid, malonic acid, succinic acid, citric acid, tartaric acid, malic acid, maleic acid, fumaric acid, adipic acid, alginic acid, aspartic acid, benzoic acid, digluconic acid, nicotinic acid, pamoic acid, pectin oic acid, glucoheptonic acid, glycerophosphoric acid, benzenesulfonic acid, tosylic acid, methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, dodecylsulfuric acid, 2-hydroxyethanesulfonic acid and 2-naphthalenesulfonic acid, etc., preferably hydrochloric acid, sulfuric acid, acetic acid, lactic acid, malic acid, citric acid, methanesulfonic acid and tosylic acid, etc.

Specific examples of the "inorganic cation" include sodium, potassium, lithium, calcium, etc., preferably sodium and potassium.

Specific examples of the "organic cation" include methylammonium, ethylammonium, dimethylammonium, diethylammonium, diisopropylammonium, pyridinium, trimethylammonium, triethylammonium, cyclohexylammonium, dicyclohexylammonium, diisopropylethylammonium, pyridinium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, triethylbenzylammonium, N,N' -dimethylimidazolium, N-methylpyridinium, etc., preferably pyridinium and tetrabutylammonium.

Specific examples of "C _1-6 alkyl" include a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, neopentyl, 1-methylbutyl, 2-methylbutyl, isopentyl and hexyl, a C _3-6 cycloalkyl group such as cyclo propyl, cyclobutyl, cyclopentyl and cyclohexyl, or a methyl group substituted with a C _3-5 cycloalkyl group such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, preferably methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl and cyclobutylmethyl.

Specific examples of "heterocyclyl" include a group derived from aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazolidine, oxazolidine, thiazolidine, pyrazolidine, piperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran, hexahydropyridazine a, piperazine, morpholine, thiomorpholine, 1,2-oxazolidine, 1,2-oxazinane, 1,4-dioxane, 1,2-thiazinan, azepan, oxepan, thiepana, 1,4-diazepane, 1,4-oxazepane, 1,4-thiazepane, 1,2,5-triazepane, 1, 4,5-oxadiazepane, 1,2,5-oxadiazepane, 1,4,5-thiadiazepane, 1,5,2-dioxazepane, 1,5,2-oxathiazepane, 3,4-dihydro-2H-pyrrole, 4,5-dihydro-1H-pyrazole, 4,5-dihydro-1H-imidazole, 4,5-dihydro-1 ,2-oxazole, 4,5-dihydro-1,3-oxazole, 4,5-dihydro-1,3-thiazole, 2,3,4,5-tetrahydropyridine, 1,2,3,6 tetrahydropyrazine, 5,6-dihydro-4H-1,2-oxazine, from 3,6-dihydro--2-H-1,4-oxazine, etc., preferably a group, obtained azetidine, pyrrolidine, tetrahydrofuran, piperidine, tetrahydro-2H-pyran, imidazolidine, oxazolidine, 1,2-oxazolidine, hexahydropyridazine, piperazine, morpholine, 1,2-oxazinane, azepane, 1,4-diazepane and 1,2-oxazepane.

Specific examples of a protecting group for "heterocyclyl" in which "t-butoxycarbonyl or benzyloxycarbonyl is linked" include a group derived from 1-(t-butoxycarbonyl)azetidine, 1-(t-butoxycarbonyl)pyrrolidine, 1,3-di(t-butoxycarbonyl)imidazolidine, 3-(t-butoxycarbonyl)oxazolidine, 1,3-di(tert-butoxycarbonyl)pyrazolidine, 1-(tert-butoxycarbonyl)piperidine, 1,2-di(tert-butoxycarbonyl)hexahydropyridazine, 1,4-di(tert-butoxycarbonyl)piperazine, 4-(tert-butoxycarbonyl)morpholine, 2-(tert-butoxycarbonyl)-1,2-oxazolidine , 2-(tert-butoxycarbonyl)-1,2-oxazinane, 1-(tert-butoxycarbonyl)azepane, 1,4-di(tert-butoxycarbonyl)-1,4-diazepane, 1-(benzyloxycarbonyl)azetidine, 1-(benzyloxycarbonyl)pyrrolidine, 1,3-di(benzyloxycarbonyl)imidazolidine, 3- (benzyloxycarbonyl)oxazolidine, 1,3-di(benzyloxycarbonyl)pyrazolidine, 1-(benzyloxycarbonyl)piperidine, 1,2-di(benzyloxycarbonyl)hexahydropyridazine, 1,4-di(benzyloxycarbonyl)piperazine, 4-(benzyloxycarbonyl)morpholine, 2-(benzyloxycarbonyl)-1,2-oxa zolidine, 2-(benzyloxycarbonyl)-1,2-oxazinane, 1-(benzyloxycarbonyl)azepane, 1,4-di(benzyloxycarbonyl)-1,4-diazepane, etc., and of course, the specific examples having the above protecting group are included in the specific examples having heterocyclyl, which are described below.

Specific examples of "heteroaryl" include a group derived from pyrrole, furan, thiophene, pyrazole, imidazole, 1,2-oxazole, 1,3-oxazole, 1,2-thiazole, 1,3-thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, 1,3 ,4-oxadiazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, etc., preferably a group derived from pyrrole, furan, imidazole, oxazole and pyridine.

Specific examples of a protecting group for "heteroaryl" to which "tert-butoxycarbonyl or benzyloxycarbonyl is bonded" include a group derived from 1-tert-butoxycarbonylpyrrole, 1-tert-butoxycarbonylpyrazole, 1-tert-butoxycarbonylimidazole, 1-tert-butoxycarbonyl-1,2,3-triazole, 1-tert-butoxy carbonyl-1,2,4-triazole, 1-tert-butoxycarbonyltetrazole, 1-benzyloxycarbonylpyrrole, 1-benzyloxycarbonylpyrazole, 1-benzyloxycarbonylimidazole, 1-benzyloxycarbonyl-1,2,3-triazole, 1-benzyloxycarbonyl-1,2,4-triazole, 1-benzyloxycarbonyl tetrazol ol, etc., and, of course, the specific examples having the above protecting group are included in the specific examples having heteroaryl, which are described below.

Specific examples of "C _1-6 alkylcarbonyl" include acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, 2,2-dimethylpropanoyl, 2-methylbutanoyl, 3-methylbutanoyl, hexanoyl, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, 2-cyclopropylacetyl, 2-cyclo butylacetyl, 2-cyclopentylacetyl, etc.

Specific examples of "heterocyclylcarbonyl" include aziridin-2-yl-carbonyl, oxiran-2-ylcarbonyl, thiiran-2-ylcarbonyl, azetidin-2-ylcarbonyl, azetidin-3-ylcarbonyl, oxetan-2-ylcarbonyl, oxetan-3-ylcarbonyl, thietan-2-ylcarbonyl, thietan-3-ylcarbonyl , pyrrolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl, tetrahydrofuran-2-ylcarbonyl, tetrahydrofuran-3-ylcarbonyl, tetrahydrothiophen-2-ylcarbonyl, tetrahydrothiophen-3-ylcarbonyl, pyrazolidin-3-ylcarbonyl, pyrazolidin-4-ylcarbonyl, 1,2-oxazolidin-3-ylcarbonyl, 1 ,2-oxazolidin-4-ylcarbonyl, 1,2-oxazolidin-5-ylcarbonyl, piperidin-2-yl-carbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl, tetrahydro-2H-pyran-2-ylcarbonyl, tetrahydro-2H-pyran-3-ylcarbonyl, tetrahydro-2H-pyran-4-ylcarbonyl, tetrahydro-2 N-thiopyran-2-ylcarbonyl, tetrahydro-2H-thiopyran-3-ylcarbonyl, tetrahydro-2H-thiopyran-4-ylcarbonyl, hexahydropyridazin-3-ylcarbonyl, hexahydropyridazin-4-ylcarbonyl, piperazin-2-ylcarbonyl, morpholin-2-ylcarbonyl, morpholin-3-ylcarbonyl, thio-morpholin-2-yl carbonyl thiomorpholin-3-ylcarbonyl -thiazinan-4-ylcarbonyl, 1,2-thiazinan-5-ylcarbonyl, 1,2-thiazinan-6-ylcarbonyl, azepan-2-ylcarbonyl, azepan-3-ylcarbonyl, azepan-4-ylcarbonyl, oxepan-2-ylcarbonyl, oxepan-3-ylcarbonyl, oxepan-4-ylcarbonyl, thiepan- 2-ylcarbonyl thiepan-3-ylcarbonyl thiepan-4-ylcarbonyl 1,4-diazepan-2-ylcarbonyl ylcarbonyl, 1,4-oxazepan-6-ylcarbonyl, 1,4-oxazepan-7-ylcarbonyl, 1,4-thiazepan-2-ylcarbonyl, 1,4-thiazepan-3-ylcarbonyl, 1,4-thiazepan-5-ylcarbonyl, 1,4-thiazepan-6-ylcarbonyl, 1,4-thiazepan-7-ylcarbonyl . ,5-oxadiazepan-6-ylcarbonyl, 1,2,5-oxadiazepan-7-ylcarbonyl, 1,4,5-thiadiazepan-2-ylcarbonyl, 1,4,5-thiadiazepan-3-ylcarbonyl, 1,5,2-dioxazepan-3-ylcarbonyl, 1,5,2-dioxazepan-4-ylcarbonyl, 1,5,2- dioxazepan-6-ylcarbonyl, 1,5,2-dioxazepan-7-ylcarbonyl, 1,5,2-oxathiazepan-3-ylcarbonyl, 1,5,2-oxathiazepan-4-ylcarbonyl, 1,5,2-oxathiazepan-6-ylcarbonyl, 1,5,2-oxathiazepan-7-ylcarbonyl, etc. Of course, specific examples include those to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group.

Specific examples of "heteroarylcarbonyl" include pyrrol-2-ylcarbonyl, pyrrol-3-ylcarbonyl, furan-2-ylcarbonyl, furan-3-ylcarbonyl, thiophen-2-ylcarbonyl, thiophen-3-ylcarbonyl, pyrazol-3-ylcarbonyl, pyrazole-4-ylcarbonyl, imidazol-2-ylcarbonyl, imidazol-4- ylcarbonyl, 1,2-oxazol-3-ylcarbonyl, 1,2-oxazol-4-yl-carbonyl, 1,2-oxazol-5-ylcarbonyl, 1,3-oxazol-2-ylcarbonyl, 1,3-oxazol-4-ylcarbonyl, 1,3-oxazol-5-ylcarbonyl, 1,2-thiazol-3-ylcarbonyl, 1,2- thiazol-4-ylcarbonyl, 1,2-thiazol-5-ylcarbonyl, 1,3-thiazol-2-ylcarbonyl, 1,3-thiazol-4-ylcarbonyl, 1,3-thiazol-5-ylcarbonyl, 1,2,3-triazol-4-ylcarbonyl, 1,2,3-oxadiazol-4-ylcarbonyl, 1,2,3-oxadiazole -5-ylcarbonyl, 1,2,3-thiadiazol-4-ylcarbonyl, 1,2,3-thiadiazol-5-ylcarbonyl, 1,2,4-triazol-3-ylcarbonyl, 1,3,4-oxadiazol-2-ylcarbonyl, 1,3,4-thiadiazol-2-ylcarbonyl, tetrazol-5-ylcarbonyl, pyridin-2-ylcarbonyl , pyridin-3-ylcarbonyl, pyridin-4-ylcarbonyl, pyridazin-3-ylcarbonyl, pyridazin-4-ylcarbonyl, pyrimidin-2-ylcarbonyl, pyrimidin-4-ylcarbonyl, pyrimidin-5-ylcarbonyl, pyrazin-2-ylcarbonyl, 1,2,4-triazin-3-ylcarbonyl, 1,2,4-tria zin-5-ylcarbonyl, 1,2,4-triazin-6-ylcarbonyl, 1,3,5-triazin-2-ylcarbonyl, etc. Of course, specific examples include those to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group.

To the above "acyl" is added formyl, benzoyl or phenylacetyl, preferably formyl, benzoyl, acetyl, phenylacetyl, propanoyl, butanoyl, 2-methylpropanoyl, 2,2-dimethylpropanoyl, azetidin-2-ylcarbonyl, azetidin-3-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl , tetrahydrofuran-3-ylcarbonyl, piperidin-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl, tetrahydro-2H-pyran-2-ylcarbonyl, tetrahydro-2H-pyran-3-ylcarbonyl, tetrahydro-2H-pyran-4-ylcarbonyl, furan-2-ylcarbonyl, 1,3-oxazol-2-ylcarbonyl , 1,3-oxazol-4-ylcarbonyl, pyridin-2-ylcarbonyl, pyridin-3-ylcarbonyl and pyridin-4-ylcarbonyl.

Specific examples of Re(RF)N- include amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, t-butylamino, sec-butylamino, iso-butylamino, pentylamino, 1,1-dimethylpropylamino, 1,2-dimethylpropylamino, neopentylamino, 1-methylbutylamino, 2-methylbutylamino, isopentylamino, hex ylamino N,N-dimethylamino N,N-diethylamino N ,N-di(1,2-dimethylpropyl)amino, N,N-di(neopentyl)amino, N,N-di(1-methylbutyl)amino, N,N-di(2-methylbutyl)amino, N,N-di(isopentyl)amino, N,N-di(hexyl)amino etc., preferably amino, methylamino, ethylamino, propylamino, isopropylamino, N,N-dimethylamino and N,N-diethylamino. Of course, specific examples include those to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group.

Specific examples of Re(Rf)NCO- include aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, t-butylaminocarbonyl, sec-butylaminocarbonyl, isobutylaminocarbonyl, pentylaminocarbonyl, 1,1-dimethylpropylaminocarbonyl, 1,2-dimethylpropylamino carbonyl, neopentylaminocarbonyl, 1-methylbutylaminocarbonyl, 2-methylbutylaminocarbonyl, isopentylaminocarbonyl, hexylaminocarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N,N-dipropylaminocarbonyl, N,N-di(isopropyl)aminocarbonyl, N,N-dibutylaminocarbonyl, N,N -di(tert-butyl)aminocarbonyl, N,N-di-(sec-butyl)aminocarbonyl, N,N-di(isobutyl)aminocarbonyl, N,N-dipentylaminocarbonyl, N,N-di(1,1-dimethylpropyl)aminocarbonyl, N,N-di(1,2-dimethylpropyl)aminocarbonyl, N,N-di(neopentyl)aminocarbonyl, N,N- di(1-methylbutyl)aminocarbonyl, N,N-di(2-methylbutyl)aminocarbonyl, N,N-di(isopentyl)aminocarbonyl, etc., which are derived from the specific examples of Re(Rf)N- described above, preferably dimethylaminocarbonyl or diethylaminocarbonyl.

Specific examples of ReO- include hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, sec-butoxy, isobutoxy, pentoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, neopentoxy, 1-methylbutoxy, 2-methylbutoxy, isopentoxy, hexyloxy, benzyloxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, etc., preferably hydroxy, methoxy, ethoxy, propoxy, isopropoxy, t-butoxy, cyclopropoxy and cyclobutylmethoxy. Of course, specific examples include those in which triisopropylsilyl is included in the trialkylsilyloxy as a protecting group.

Specific examples of ReOCO- include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, sec-butoxycarbonyl, iso-butoxycarbonyl, pentoxycarbonyl, 1,1-dimethylpropoxycarbonyl, 1,2-dimethylpropoxycarbonyl, neopentoxycarbonyl, 1-methylbutoxycarbonyl, 2-methylbutoxycarbonyl, isopentoxycarbonyl, hexyloxycarbonyl, etc., which are derived from the specific examples of ReO- described above, preferably methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and benzyloxycarbonyl, phenyl-modified methoxycarbonyl, which is defined by Fn1.

Specific examples of RdO ₂ S- include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, t-butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, neopentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl onyl, isopentylsulfonyl, hexylsulfonyl, cyclopropanesulfonyl, cyclobutanesulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cyclopropylmethanesulfonyl, cyclobutylmethanesulfonyl, cyclopentylmethanesulfonyl, etc., preferably sulfoxy and methanesulfonyl.

Конкретные примеры Ra(Rb)N- включают указанный выше С _1-6 алкил, ацил и Re(Rf)N-, предпочтительно, амино, метиламино, этиламино, пропиламино, изопропиламино, трет-бутиламино, изобутиламино, N,N-диметиламино, N,N-диэтиламино, N,N-ди(изопропил)амино, ацетиламино, пропаноиламино, изобутаноиламино, фенилацетиламино, бензоиламино, [(азетидин-2-ил)карбонил]амино, [(азетидин-3-ил)карбонил]амино, [(пирролидин-2-ил)карбонил]амино, [(пирролидин-3-ил)карбонил]амино, [(тетрагидрофуран-3-ил)карбонил]амино, [(тетрагидротиофен-3-ил)карбонил]амино, [(пиразолидин-3-ил)карбонил]амино, [(пиразолидин-4-ил)карбонил]амино, [(1,2-оксазолидин-3-ил)карбонил]амино, [(пиперидин-2-ил)карбонил]амино, [(пиперидин-3-ил)карбонил]амино, [(пиперидин-4-ил)карбонил]амино, [(тетрагидро-2Н-пиран-2-ил)карбонил]амино, [(тетрагидро-2Н-пиран-4-ил)карбонил]амино, [(тетрагидро-2Н-тиопиран-4-ил)карбонил]амино, [(гексагидропиридазин-3-ил)карбонил]амино, [(гексагидропиридазин-4-ил)карбонил]амино, [(пиперазин-2-ил)карбонил]амино, [(морфолин-2-ил)карбонил]амино, [(морфолин-3-ил)карбонил]амино, [(тиоморфолин-2-ил)карбонил]амино, [(тиоморфолин-3-ил)карбонил]амино, [(1,2-оксазинан-3-ил)карбонил]амино, [(азепан-2-ил)карбонил]амино, [(азепан-4-ил)карбонил]амино, [(оксепан-2-ил)карбонил]амино, [(оксепан-4-ил)карбонил]амино, [(1,4-диазепан-2-ил)карбонил]амино, [(1,4-диазепан-6-ил)карбонил]амино, пиррол-2-илкарбониламино, пиррол-3-илкарбониламино, фуран-2-илкарбониламино, фуран-3-илкарбониламино, пиразол-3-илкарбониламино, пиразол-4-илкарбониламино, имидазол-2-илкарбониламино, имидазол-4-илкарбониламино, 1,2-оксазол-3-илкарбониламино, 1,2-оксазол-4-илкарбониламино, 1,2-оксазол-5-илкарбониламино, 1,3-оксазол-2-илкарбониламино, 1,3-оксазол-4-илкарбониламино, 1,3-оксазол-5-илкарбониламино, 1,3-тиазол-2-илкарбониламино, 1,3-тиазол-4-илкарбониламино, 1,3-тиазол-5-илкарбониламино, 1,2,3-триазол-4-илкарбониламино, 1,2,3-триазол-5-илкарбониламино, 1,2,3-оксадиазол-4-илкарбониламино, 1,2,3-оксадиазол-5-илкарбониламино, 1,2,4-триазол-3-илкарбониламино, 1,3,4-оксадиазол-3-илкарбониламино, тетразол-5-илкарбониламино, пиридин-2-илкарбониламино, пиридин-3-илкарбониламино, пиридин-4-илкарбониламино, пиридазин-3-илкарбониламино, пиридазин-4-илкарбониламино, пиримидин-2-илкарбониламино, пиримидин-4-илкарбониламино, пиразин-2-илкарбониламино, 1,2,4-триазин-3-илкарбониламино, 1,2,4-триазин-5-илкарбониламино, 1,2,4-триазин-6-илкарбониламино, 1,3,5-триазин-2-илкарбониламино и т.д. In addition, specific examples of variants where Ra and Rb from Ra(Rb)N- are coupled to form heterocyclyl include azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, 2-oxoazetidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxoazepan-1-yl, etc. .d. Of course, the above specific examples include those to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group.

Предпочтительные конкретные примеры С _1-6 алкокси, представленные конкретными примерами указанного выше ReO- и RсO-, полученными из гетероциклила, включают метокси, этокси, пропокси, изопропокси, циклобутилметокси, азетидин-3-илокси, оксетан-3-илокси, тиетан-3-илокси, пирролидин-3-илокси, тетрагидрофуран-3-илокси, тетрагидротиофен-3-илокси, пиразолидин-4-илокси, пиперидин-3-илокси, пиперидин-4-илокси, тетрагидро-2Н-пиран-3-илокси, тетрагидро-2Н-пиран-4-илокси, тетрагидро-2Н-тиопиран-3-илокси, тетрагидро-2Н-тиопиран-4-илокси, гексагидропиридазин-4-илокси, 1,2-оксазолидин-4-илокси, 1,2-оксазинан-4-илокси, 1,2-оксазинан-5-илокси, 1,2-тиазинан-4-илокси, 1,2-тиазинан-5-илокси, азепан-3-илокси, азепан-4-илокси, оксепан-3-илокси, оксепан-4-илокси, тиепан-3-илокси, тиепан-4-илокси, 1,4-диазепан-6-илокси, 1,4-оксазепан-6-илокси, 1,4-тиазепан-6-илокси и т.д. In addition, in RcO-B-, specific examples of heterocyclyl formed by coupling of the Rc ring and B include 1,2-oxazolidine, 1,2-oxazinane, 1,2-oxazepane, etc. Of course, the above specific examples include those to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group.

Further, detailed examples of the variant in which C _1-6 alkyl, acyl or heterocyclyl, which form the above Ra(Rb)N- or RcO-, is modified with C _1-6 alkyl, O=, Rg-(CH ₂ ) _0-3 -, heterocyclyl, phenyl, heteroaryl, acyl, RdO ₂ S-, Re(Rf)N-, Re(Rf)NCO-, ReO- and ReOCO-, which defined by Fn1 or a protecting group are described in more detail in the Representative Examples, but, of course, the examples are not limited to the scope of the specific examples that are illustrated.

Specific examples of C _1-6 alkyl modified amino (H ₂ N-), which is an example of Re(Rf)N-, include 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 2-amino-1-methylethyl, 2-aminobutyl, 3-aminobutyl, 4-aminobutyl, 2-amino-1,1-dimethylethyl, 2-amino-1-methylpropyl, 3-ami no-2-methylpropyl, etc. Of course, variants to which a protective tert-butoxycarbonyl or benzyloxycarbonyl is attached, which are included in ReOCO-, are included in the above specific examples.

In addition, CH ₂ to which amino is attached, in 2-aminoethyl in the above specific examples, is modified with O= (oxo) to obtain an aminocarbonylalkyl derivative included in Re(Rf)NCO-, includes 2-(amino)-2-oxoethyl, 2-(methylamino)-2-oxoethyl, 2-(ethylamino)-2-oxoethyl, 2-oxo-2-(propylamino)ethyl , 2-(isopropylamino)-2-oxoethyl, 2-(tert-butylamino)-2-oxoethyl, 2-(isobutylamino)-2-oxoethyl, etc.

In addition, specific examples in which the above 2-aminoethyl derivative is modified with methylsulfonyl as a typical example of RdO₂S-, acetyl as a typical example of acyl or carbamoyl (H₂NCO-), as a typical example of Re(Rf)NCO-, includes 2-(methylsulfonylamino)ethyl, 2-(methylsulfonylamino)propyl, 3-(methylsulfonylamino)propyl, 2-(methylsulfonylamino)-1-methylethyl, 2-(methylsulfonylamino)butyl, 3-(methylsulfonylamino)butyl, 4-(methylsulfonylamino)butyl, 2-(methylsulfonylamino)-1 ,1-dimethylethyl, 2-(methylsulfonylamino)-1-methylpropyl, 3-(methylsulfonylamino)-2-methylpropyl, 2-(acetylamino)ethyl, 2-(acetylamino)propyl, 3-(acetylamino)propyl, 2-(acetylamino)-1-methylethyl, 2-(acetylamino)butyl, 3-(acetylamino)butyl, 4-(acetylamino)butyl, 2-(acetylamino)-1,1-dimethylethyl, 2-(acetylamino)-1-methylpropyl, 3-(acetylamino)-2-methylpropyl, 2-(carbamoylamino)ethyl, 2-(carbamoylamino)propyl, 3-(carbamoylamino)propyl, 2-(carbamoylamino)-1-methylethyl, 2-(carbamoylamino)butyl, 3-(car bamoylamino)butyl, 4-(carbamoylamino)butyl, 2-(carbamoylamino)-1,1-dimethylethyl, 2-(carbamoylamino)-1-methylpropyl, 3-(carbamoylamino)-2-methylpropyl, etc.

Specific examples in which C _1-6 alkyl is modified with hydroxy (HO-) as a typical example of ReO- include 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-1-methylethyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 2-hydroxy-1-methylpropyl, 3-hydroxy-2-methylpropyl, etc. Of course, the above specific examples include those in which the hydroxy is protected by triisopropylsilyl included in the trialkylsilyl.

Specific examples of the variant in which ethyl typified by C _1-6 alkyl is modified with methylsulfonyl typified by RdO ₂ S— include 2-(methylsulfonyl)ethyl.

Конкретные примеры, в которых С _1-6 алкилкарбонил, фенилацетил или бензоил, модифицированы амино (H ₂ N-) в качестве типового примера Re(Rf)N-, включают 2-аминоацетил, 2-аминопропаноил, 3-аминопропаноил, 2-аминобутаноил, 3-аминобутаноил, 4-аминобутаноил, 3-амино-2-метилпропаноил, 2-(2-аминофенил)ацетил, 2-(3-аминофенил)ацетил, 2-(4-аминофенил)ацетил, 2-[2-(аминометил)фенил]ацетил, 2-[3-(аминометил)фенил]ацетил, 2-[4-(аминометил)фенил]ацетил, 2-аминобензоил, 3-аминобензоил, 4-аминобензоил, 2-(аминометил)бензоил, 3-(аминометил)бензоил, 4-(аминометил)бензоил и т.д. Of course, examples to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group are included in the specific examples.

Specific examples of C _1-6 alkylcarbonyl, phenylacetyl or benzoyl modified with hydroxyl (HO-) as a typical example of ReO- include 2-hydroxyacetyl, 2-hydroxypropanoyl, 3-hydroxypropanoyl, 2-hydroxybutanoyl, 3-hydroxybutanoyl, 4-hydroxybutanoyl, 3-hydroxy-2-methylpropanoyl, 2-(2-hydroxyphenyl)acetyl, 2 -(3-hydroxyphenyl)acetyl, 2-(4-hydroxyphenyl)acetyl, 2-hydroxybenzoyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, etc. Of course, examples in which hydroxy is protected by triisopropylsilyl included in the trialkylsilyl are included in the above specific examples.

Конкретные примеры, в которых метил или этил в качестве типовых примеров С _1-6 алкила модифицированы гетероциклилом, включают азетидин-2-илметил, азетидин-3-илметил, пирролидин-2-илметил, пирролидин-3-илметил, тетрагидрофуран-3-илметил, тетрагидротиофен-3-илметил, пиразолидин-4-илметил, 1,2-оксазолидин-3-илметил, пиперидин-2-илметил, пиперидин-3-илметил, пиперидин-4-илметил, тетрагидро-2Н-пиран-4-илметил, тетрагидро-2Н-тиопиран-4-илметил, гексагидропиридазин-4-илметил, пиперазин-2-илметил, 1,2-оксазинан-3-илметил, морфолин-2-илметил, морфолин-3-илметил, тиоморфолин-2-илметил, тиоморфолин-3-илметил, азепан-2-илметил, азепан-4-илметил, оксепан-2-илметил, оксепан-4-илметил, 1,4-диазепан-2-илметил, 1,4-диазепан-6-илметил, 2-(азетидин-1-ил)этил, 2-(пирролидин-1-ил)этил, 2-(пиразолидин-1-ил)этил, 2-(пиперидин-1-ил)этил, 2-(гексагидропиридазин-1-ил)этил, 2-(пиперазин-1-ил)этил, 2-(морфолин-4-ил)этил, 2-(тиоморфолин-4-ил)этил, 2-(1,2-оксазолидин-2-ил)этил, 2-(1,2-оксазинан-2-ил)этил, 2-(азепан-1-ил)этил, 2-(1,4-диазепан-1-ил)этил и т.д. Of course, examples to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group are included in the specific examples.

In addition, specific examples in which ethyl from the above heterocyclylethyl derivative is modified with O=(oxo) to give an aminocarbonyl incorporated in Re(Rf)NCO- include 2-(azetidin-1-yl)oxoethyl, 2-oxo-(pyrrolidin-1-yl)ethyl, 2-oxo-(pyrazolidin-1-yl)ethyl, 2-oxo-(piperidin-1-yl)ethyl, 2-(hexahydropyridazin-1-yl)-2-oxoethyl, 2-oxo-(piperazin-1-yl)ethyl, 2-(morpholin-4-yl)-2-oxoethyl, 2-oxo-(thiomorpholin-4-yl)ethyl, 2-(1,2-oxazolidin-2-yl)-2-oxoethyl, 2-(1,2-oxazinan-2-yl)-2-oxo ethyl, 2-(azepan-1-yl)-2-oxoethyl, 2-(1,4-diazepan-1-yl)-2-oxoethyl, etc. Of course, the above examples include those to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group.

Specific examples in which in Re(Rf)NCO-, Re and Rf modified with Fn1 are coupled to give heterocyclyl include azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, 1,2-oxazolidin-2-ylcarbonyl, pyrazolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, hexahydropyridazin-1-ylcarbonyl, pi perazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, thiomorpholin-4-ylcarbonyl, 1,2-oxazinan-2-ylcarbonyl, azepan-1-ylcarbonyl, 1,4-diazepan-1-ylcarbonyl, etc.

Конкретные примеры, в которых метил или этил в качестве типовых примеров С _1-6 алкила модифицированы гетероарилом, включают пиррол-2-илметил, фуран-2-илметил, пиразол-3-илметил, пиразол-4-илметил, имидазол 2-илметил, имидазол-4-илметил, 1,2-оксазол-3-илметил, 1,3-оксазол-2-илметил, 1,3-оксазол-4-илметил, 1,3-тиазол-2-илметил, 1,3-тиазол-4-илметил, 1,2,3-триазол-4-илметил, 1,2,3-оксадиазол-4-илметил, 1,2,4-триазол-3-илметил, 1,3,4-оксадиазол-2-илметил, тетразол-5-илметил, пиридин-2-илметил, пиридин-3-илметил, пиридин-4-илметил, пиридазин-3-илметил, пиридазин-4-илметил, пиримидин-2-илметил, пиримидин-4-илметил, пиразин-2-илметил, 1,2,4-триазин-3-илметил, 1,2,4-триазин-5-илметил, 1,3,5-триазин-2-илметил, 2-(пиррол-1-ил)этил, 2-(пиразол-1-ил)этил, 2-(имидазол-1-ил)этил, 2-(1,2,3-триазол-1-ил)этил, 2-(1,2,4-триазол-4-ил)этил, 2-(тетразол-1-ил)этил и т.д. Of course, the above examples include those to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group.

Specific examples in which heterocyclyl is modified with methyl as typical examples of C _1-6 alkyl include 1-methylazetidine, 3-methylazetidine, 1-methylpyrrolidine, 3-methylpyrrolidine, 1-methylimidazolidine, 3-methyloxazolidine, 1-methylpyrazolidine, 1-methylpiperidine, 4-methylpiperidine, 2-methyltetrahydro-2H -pyran, 4-methyltetrahydro-2H-pyran, 1-methylpiperazine, 1,4-dimethylpiperazine, 4-methylmorpholine, 4-methylthiomorpholine, 1-methylazepane, 1-methyl-1,4-diazepane, 1,4-dimethyl-1,4-diazepane, etc. Of course, the above examples include those to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group.

Specific examples of O=(oxo) modified heterocyclyl include 2-oxoazetidine, 2-oxopyrrolidine, 3-oxopyrazolidine, 2-oxoimidazolidine, 3-oxo-1,2-oxazolidine, 2-oxooxazolidine, 2-oxopiperidine, 3-oxohexahydropyridazine, 2-oxopiperazine, 3-oxomorpholine , 3-oxo-1,2-oxazinan, 2-oxoazepane, 2-oxo-1,4-diazepane, 5-oxo-1,4-diazepane, etc.

Specific examples in which ethyl is typified C_1-6 alkyl is modified with heterocyclyl, where heterocyclyl is modified with O=(oxo), include 2-(2-oxoazetidin-1-yl)ethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, 2-(2-oxoimidazolidin-3-yl)ethyl, 2-(2-oxooxazolidin-3-yl)ethyl, 2-(3-oxopyrazolidin-1-yl)ethyl, 2-( 2-oxopiperidin-1-yl)ethyl, 2-(3-oxohexahydropyridazin-1-yl)ethyl, 2-(2-oxopiperazin-1-yl)ethyl, 2-(3-oxomorpholin-4-yl)ethyl, 2-(3-oxo-1,2-oxazolidin-2-yl)ethyl, 2-(3-oxo-1,2-oxazinan-2-yl)ethyl, 2-( 2-oxoazepan-1-yl)ethyl, 2-(2-oxo-1,4-diazepan-1-yl)ethyl, 2-(5-oxo-1,4-diazepan-1-yl)ethyl, etc.

Specific examples of heterocyclylcarbonyl in which heterocyclyl is modified with O=(oxo) include 4-oxoazetidin-2-ylcarbonyl, 5-oxopyrrolidin-2-ylcarbonyl, 2-oxoimidazolidin-4-ylcarbonyl, 2-oxooxazolidin-4-ylcarbonyl, 5-oxopyrazolidin-3-ylcarbonyl, 6-oxopiperidin-2- ylmethyl, 2-oxopiperidin-4-ylcarbonyl, 6-oxohexahydropyridazin-3-ylcarbonyl, 3-oxohexahydropyridazin-4-ylcarbonyl, 5-oxopiperazin-2-ylcarbonyl, 6-oxopiperazin-2-ylcarbonyl, 5-oxomorpholin-2-ylcarbonyl, 5-oxomorpholin-3-ylcarbonyl, 3-ok sothiomorpholin-2-ylcarbonyl, 5-oxothiomorpholin-3-ylcarbonyl, 7-oxoazepan-2-ylcarbonyl, 2-oxoazepan-4-ylcarbonyl, 7-oxo-1,4-diazepan-2-ylcarbonyl, 2-oxo-1,4-diazepan-6-ylcarbonyl, etc. Of course, the above examples include those to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group.

Specific examples of heterocyclyl modified amino (H ₂ N-) as a typical example of Re(Rf)N- include a group derived from 3-aminoazetidine, 3-aminopyrrolidine, 3-aminotetrahydrofuran, 3-aminotetrahydrothiophene, 4-aminopyrazolidine, 4-aminopiperidine, 4-aminotetrahydro-2H-pyran, 4-amino tetrahydro-2H-thiopyran, 4-aminohexahydropyridazine, 4-amino-1,2-oxazolidine, 4-amino-1,2-oxazinan, 4-aminoazepane, 4-aminooxepane, 6-amino-1,4-diazepane, etc. Of course, the above examples include those to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group.

Specific examples of heterocyclyl modified with hydroxy (HO-) as a typical example of ReO- include a group derived from 3-hydroxyazetidine, 3-hydroxypyrrolidine, 4-hydroxypyrazolidine, 4-hydroxytetrahydrofuran, 4-hydroxytetrahydrothiophene, 3-hydroxypiperidine, 4-hydroxypiperidine, 4-hydroxytetrahydro-2H-thiopyran, 4-hydroxyhexahydropyride zine, 4-hydroxy-1,2-oxazolidine, 4-hydroxy-1,2-oxazinan, 4-hydroxyazepane, 6-hydroxy-1,4-diazepane, etc. Of course, the above specific examples include those in which the hydroxy group is protected by triisopropylsilyl, the heterocyclyl is protected by t-butoxycarbonyl or benzyloxycarbonyl.

Конкретные примеры гетероарила, модифицированного метилом в качестве типовых примеров С _1-6 алкила, включают группу, полученную из 1-метилпиррола, 2-метилпиррола, 3-метилпиррола, 1-метилпиразола, 3-метилпиразола, 4-метилпиразола, 2-метилимидазола, 4-метилимидазола, 4-метил-1,2-оксазола, 5-метил-1,2-оксазола, 2-метил-1,3-оксазола, 4-метил-1,3-оксазола, 5-метил-1,3-оксазола, 1-метил-1,2,3-триазола, 4-метил-1,2,3-триазола, 1-метил-1,2,4-триазола, 3-метил-1,2,4-триазола, 1-метилтетразола, 5-метилтетразола, 2-метил-1,3,4-оксадиазола, 2-метилпиридина, 3-метилпиридина, 4-метилпиридина, 3-метилпиридазина, 4-метилпиридазина, 2-метилпиримидина, 4-метилпиримидина, 2-метилпиразина, 3-метил-1,2,4-триазина, 5-метил-1,2,4-триазина, 6-метил-1,2,4-триазина, 2-метил-1,3,5-триазина и т.д. Of course, the above examples include those to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group.

Конкретные примеры гетероарила, модифицированного амино (H ₂ N-) в качестве типового примера Re(Rf)N-, включают группу, полученную 2-аминопиррола, 3-аминопиррола, 2-аминофурана, 3-аминофурана, 3-аминопиразола, 4-аминопиразола, 2-аминоимидазола, 3-амино-1,2-оксазола, 2-амино-1,3-оксазола, 2-аминотиазола, 4-амино-1,2,3-триазола, 3-амино-1,2,4-триазола, 2-амино-1,3,4-тиадиазола, 5-аминотетразола, 2-амино-1,3,4-оксадиазола, 2-аминопиридина, 3-аминопиридазина, 2-аминопиримидина, 3-амино-1,2,4-триазина, 2-амино-1,3,5-триазина и т.д. Of course, the above examples include those to which tert-butoxycarbonyl or benzyloxycarbonyl is attached as a protecting group.

Specific examples of heteroaryl modified with hydroxy (HO-) as a typical example of ReO- include the group derived from 2-hydroxypyrrole, 3-hydroxypyrrole, 2-hydroxyfuran, 3-hydroxyfuran, 3-hydroxypyrazole, 4-hydroxypyrazole, 2-hydroxyimidazole, 3-hydroxy-1,2-oxazole, 2-hydroxy-1,3-oxazole, 2-hydroxythiazole, 4-hydroxy-1,2,3-triazole, 3-hydroxy-1,2,4-triazole, 5-hydroxytetrazole, 2-hydroxy-1,3,4-oxadiazole, 2-hydroxypyridine, 3-hydroxypyridazine, 2-hydroxypyrimidine, 3-hydroxy-1,2,4-triazine, 2-hydroxy-1,3,5-triazine, etc. Of course, the above specific examples include those in which the hydroxy group is protected by triisopropylsilyl and the heteroaryl is protected by t-butoxycarbonyl or benzyloxycarbonyl.

В качестве конкретных примеров Ra(Rb)N-, содержащего указанный выше С _1-6 алкил или ацил, предпочтительными являются амино, метиламино, этиламино, пропиламино, изопропиламино, диметиламино, диэтиламино, фениламино, ацетиламино, пропаноиламино, бутаноиламино, 2-метилпропаноиламино, 2,2-диметилпропаноиламино, 2-аминоацетиламино, 3-аминопропаноиламино, 2-метоксиацетиламино, фенилацетиламино, 2-(4-аминофенил)ацетиламино, 2-(4-аминометилфенил)ацетиламино, бензоиламино, 4-аминобензоиламино, 4-аминометилбензоиламино, [(азетидин-2-ил)карбонил]амино, [(пирролидин-2-ил)карбонил]амино, [(пирролидин-3-ил)карбонил]амино, [(пиперидин-2-ил)карбонил]амино, [(пиперидин-3-ил)карбонил]амино, [(пиперидин-4-ил)карбонил]амино, [(4-циклопентилметилпиперидин-2-ил)карбонил]амино, [(тетрагидро-2Н-пиран-4-ил)карбонил]амино, [(5-оксопирролидин-2-ил)карбонил]амино, фуран-2-илкарбониламино, 1,3-оксазол-4-илкарбониламино, пиридин-2-илкарбониламино, пиридин-3-илкарбониламино, пиридин-4-илкарбониламино, метансульфониламино, диметиламинокарбониламино, диэтиламинокарбониламино, фениламинокарбониламино, морфолин-4-илкарбониламино, метоксикарбониламино, этоксикарбониламино, трет-бутоксикарбониламино и т.д. In addition, specific examples for variants in which Ra(Rb)N-, Ra and Rb modified with Fn1 are associated with heterocyclyl production include azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, azepan-1-yl, 1,4-diazepan-1-yl, 2-oc soazetidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxopiperazin-1-yl, 3-oxomorpholin-4-yl, 2-oxoazepan-1-yl, 2-oxo-1,4-diazepan-1-yl, etc. Of course, free NH or HO modified with a protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or triisopropylsilyl are included in the above Ra(Rb)N-, if necessary.

Кроме того конкретные примеры RcO-, включающей указанные выше С _1-6 алкокси и гетероциклилокси, включают, предпочтительно, метокси, этокси, пропокси, изопропокси, циклобутилметокси, азетидин-3-илокси, пирролидин-3-илокси, тетрагидрофуран-3-илокси, тетрагидротиофен-3-илокси, пиразолидин-4-илокси, пиперидин-3-илокси, пиперидин-4-илокси, тетрагидро-2Н-пиран-4-илокси, тетрагидро-2Н-тиопиран-4-илокси, 1,2-оксазолидин-4-илокси, 1,2-оксазинан-4-илокси, 1,2-оксазинан-5-илокси, азепан-3-илокси, азепан-4-илокси, 1,4-диазепан-6-илокси, 1,4-оксазепан-6-илокси, 2-аминоэтокси, 2-(метиламино)этокси, 2-(пропиламино)этокси, 2-(изопропиламино)этокси, 2-(диметиламино)этокси, 2-гидроксиэтокси, 2-метоксиэтокси, 2-аминопропокси, 3-аминопропокси, 2-амино-1-метилэтокси, 2-амино-2-оксоэтокси, 2-(диметиламино)-2-оксоэтокси, 2-(метилсульфонил)этокси, (азетидин-2-ил)метокси, (азетидин-3-ил)метокси, (пирролидин-2-ил)метокси, (пирролидин-3-ил)метокси, (пиперидин-2-ил)метокси, (пиперидин-3-ил)метокси, (пиперидин-4-ил)метокси, (4-оксоазетидин-2-ил)метокси, (5-оксопирролидин-2-ил)метокси, (6-оксопиперидин-2-ил)метокси, 2-(азетидин-1-ил)этокси, 2-(пирролидин-1-ил)этокси, 2-(пиперидин-1-ил)этокси, 2-(морфолин-4-ил)этокси, 2-(пиперазин-1-ил)этокси, 2-(1,4-диазепан-1-ил)этокси, 2-(азетидин-1-ил)-2-оксоэтокси, 2-оксо-2-(пирролидин-1-ил)этокси, 2-оксо-2-(пиперидин-1-ил)этокси, 2-оксо-2-(пиперазин-1-ил)этокси, 2-(морфолин-4-ил)-2-оксоэтокси, 2-(1,4-диазепан-1-ил)-2-оксоэтокси, 2-(2-оксоазетидин-1-ил)этокси, 2-(2-оксопирролидин-1-ил)этокси, 2-(2-оксопиперидин-1-ил)этокси, 2-(2-оксоимидазолидин-1-ил)этокси, 2-(2-оксо-1,3-оксазолидин-3-ил)этокси, 2-(пиррол-1-ил)этокси, 2-(имидазол-1-ил)этокси, 2-(2-сульфонат-1Н-имидазол-1-ий-1-ил)этокси. In addition, specific examples of heterocyclyl obtained by combining Rc and B or Rc and B modified with Fn1 in RcO-B- include 1,2-oxazolidin-2-yl, 1,2-oxazinan-2-yl, 1,2-oxazepan-2-yl, 1,2,5-oxadiazepan-2-yl, 1,5,2-dioxazepan-5-yl, etc. Of course, free NH or HO modified with a protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or triisopropylsilyl are included in the above RcO-, if necessary.

More specific examples of compounds provided in accordance with this invention include the following compounds:

(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

tert-butyl 2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,

tert-butyl 2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,

tetrabutylammonium tert-butyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate tetrabutylammonium,

sodium tert-butyl 1-methyl-2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,

tert-butyl 2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate,

tert-butyl 2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate,

tert-butyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazine pyridinium carboxylate,

(2S,5R)-N'-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N',N'-dimethyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-6-benzyloxy-N',N'-dimethyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N',N'-dimethyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N',N'-dimethyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carbohydrazide,

(2S,5R)-N'-acetyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-N'-acetyl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-acetyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-acetyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide tetrabutylammonium,

(2S,5R)-7-oxo-6-N'-propanoyl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo-N'-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-6-hydroxy-7-oxo-N'-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-7-oxo-N'-propanoyl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carbohydrazide,

(2S,5R)-N'-(2-methylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-6-benzyloxy-N'-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-6-hydroxy-N'-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-(2-methylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carbohydrazide,

(2S,5R)-N'-(2,2-dimethylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-6-benzyloxy-N'-(2,2-dimethylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-(2,2-dimethylpropanoyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-(2,2-dimethylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carbohydrazide,

(2S,5R)-N'-acetyl-N'-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-N'-acetyl-6-benzyloxy-N'-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-acetyl-6-hydroxy-N'-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R) -N'-acetyl-N'-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carbohydrazide,

(2S,5R)-N'-(aminoacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

tert-butyl [2(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]carbamate,

tert-butyl [2(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]carbamate,

tert-butyl [2-(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]pyridinium carbamate,

(2S,5R)-N'-(3-aminopropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

tert-butyl [3-(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-3-oxopropyl]carbamate,

tert-butyl [3-(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-3-oxopropyl]carbamate,

tert-butyl [3-(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-3-oxopropyl]pyridinium carbamate,

(2S,5R)-N'-[(4-aminophenyl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

tert-butyl {4-[2-(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]phenyl}carbamate,

tert-butyl {4-[2-(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]phenyl}carbamate,

tert-butyl {4-[2-(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]phenyl}tetrabutylammonium carbamate,

(2S,5R)-N'-(methoxyacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-6-benzyloxy-N'-(methoxyacetyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-6-hydroxy-N'-(methoxyacetyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-(methoxyacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carbohydrazide,

(2S,5R)-N'-benzoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-N'-benzoyl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-benzoyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-benzoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide pyridinium,

(2S,5R)-N'-(4-aminobenzoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

tert-butyl {4-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]phenyl}carbamate,

tert-butyl {4-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]phenyl}carbamate,

tert-butyl {4-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]phenyl}tetrabutylammonium carbamate,

(2S,5R)-N'-(4-(aminomethyl)benzoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

tert-butyl {4-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]benzyl}carbamate,

tert-butyl {4-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]benzyl}carbamate,

tert-butyl {4-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]benzyl}pyridinium carbamate,

(2S,5R)-7-oxo-N-(2-oxopyrrolidin-1-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-7-oxo-N-(2-oxopyrrolidin-1-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-7-oxo-N-(2-oxopyrrolidin-1-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-N-(2-oxopyrrolidin-1-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium,

(2S,5R)-7-oxo-6-(sulfooxy)-N'-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-6-benzyloxy-7-oxo-N'-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-6-hydroxy-7-oxo-N'-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-7-oxo-6-(sulfooxy)-N'-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide pyridinium,

(2S,5R)-7-oxo-N'-(piperidin-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

tert-Butyl 4-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,

tert-butyl 4-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,

tert-Butyl 4-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-pyridinium carboxylate,

(2S,5R)-7-oxo-N'-[(2S)-piperidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

tert-Butyl (2S)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,

tert-Butyl (2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,

tert-Butyl (2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate tetrabutylammonium,

(2S,5R)-7-oxo-N'-[(2R)-piperidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

tert-butyl (2R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,

tert-Butyl (2R)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,

tert-Butyl (2R)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate tetrabutylammonium,

(2S,5R)-7-oxo-N'-[(2S)-pyrrolidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

tert-butyl (2S)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate,

tert-butyl (2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate,

tert-Butyl (2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate tetrabutylammonium,

(2S,5R)-7-oxo-N'-[(2R)-pyrrolidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

tert-butyl (2R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate,

tert-butyl (2R)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate,

tert-Butyl (2R)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidin-1-carboxylate tetrabutylammonium,

(2S,5R)-N'-{[(2S,4R)-4-cyclopropylmethylpiperidin-2-yl]carbonyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

tert-butyl (2S,4R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-4-cyclopropylmethylpiperidine-1-carboxylate,

tert-Butyl (2S,4R)-4-cyclopropylmethyl-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,

tert-Butyl (2S,4R)-4-cyclopropylmethyl-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate tetrabutylammonium,

(2S,5R)-7-oxo-N'-{[(2S)-5-oxopyrrolidin-2-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

tert-butyl (2S)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate,

tert-butyl (2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate,

tert-butyl (2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate tetrabutylammonium,

(2S,5R)-7-oxo-N'-{[(2R)-5-oxopyrrolidin-2-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

tert-butyl (2R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate,

tert-butyl (2R)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate,

tert-butyl (2R)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-tetrabutylammonium carboxylate,

(2S,5R)-N'-(furan-2-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-6-benzyloxy-N'-(furan-2-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-(furan-2-ylcarbonyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-(furan-2-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide pyridinium,

(2S,5R)-N'-(1,3-oxazol-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-6-benzyloxy-N'-(1,3-oxazol-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-6-hydroxy-N'-(1,3-oxazol-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-(1,3-oxazol-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide pyridinium,

(2S,5R)-7-oxo-N'-(pyridin-3-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-6-benzyloxy-7-oxo-N'-(pyridin-3-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-6-hydroxy-7-oxo-N'-(pyridin-3-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-7-oxo-N'-(pyridin-3-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carbohydrazide,

(2S,5R)-7-oxo-N'-(pyridin-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-6-benzyloxy-7-oxo-N'-(pyridin-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-6-hydroxy-7-oxo-N'-(pyridin-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-7-oxo-N'-(pyridin-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carbohydrazide,

N,N-dimethyl-2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide sodium,

2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-dimethylhydrazinecarboxamide,

2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-dimethylhydrazinecarboxamide,

2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-dimethylhydrazinecarboxamide pyridinium,

N,N-diethyl-2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide sodium,

2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-diethylhydrazinecarboxamide,

N,N-diethyl-2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide,

Pyridinium N,N-diethyl-2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide,

2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide sodium,

2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide,

2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide,

2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide pyridinium,

(2S,5R)-N'-(morpholin-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-6-benzyloxy-N'-(morpholin-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-6-hydroxy-N'-(morpholin-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-(morpholin-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide pyridinium,

sodium methyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate sodium,

methyl 2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,

methyl 2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,

tetrabutylammonium methyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate tetrabutylammonium,

sodium ethyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,

ethyl 2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,

ethyl 2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,

ethyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}pyridinium hydrazinecarboxylate,

tert-butyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate sodium,

tert-butyl 2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,

tert-butyl 2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,

tert-Butyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}pyridinium hydrazinecarboxylate,

(2S,5R)-N'-(methylsulfonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium,

(2S,5R)-6-benzyloxy-N'-(methylsulfonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-6-hydroxy-N'-(methylsulfonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,

(2S,5R)-N'-(methylsulfonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carbohydrazide,

(2S,5R)-N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium,

(2S,5R)-N-methoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-N-methoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-N-methoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-methoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide tetrabutylammonium,

(2S,5R)-N-ethoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-N-ethoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-ethoxy-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-ethoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium,

(2S,5R)-N-(cyclobutylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-N-(cyclobutylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-(cyclobutylmethoxy)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-(cyclobutylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carboxamide,

(2S,5R)-N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,

tert-butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,

tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}tetrabutylammonium carbamate,

tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}pyridinium carbamate,

tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate sodium,

(2S,5R)-N-[2-(methylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamate,

tert-butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamate,

tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}tetrabutylammonium methylcarbamate,

(2S,5R)-N-[2-(ethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}ethylcarbamate,

tert-butyl ethyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,

tert-butyl tetrabutylammonium {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}ethylcarbamate,

(2S,5R)-7-oxo-N-[2-(propylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propyl carbamate,

tert-butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propyl carbamate,

tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propyl tetrabutylammonium carbamate,

(2S,5R)-7-oxo-N-[2-(propan-2-ylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propan-2-ylcarbamate,

tert-butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propan-2-ylcarbamate,

tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}tetrabutylammonium propan-2-ylcarbamate,

(2S,5R)-N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-benzyloxy-N-[2-(dimethylamino)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(dimethylamino)ethoxy]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium,

(2S,5R)-N-{[(2S)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {(2S)-1-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-2-yl}carbamate,

tert-butyl {(2S)-1-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-2-yl}carbamate,

tert-butyl {(2S)-1-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}tetrabutylammonium carbamate,

(2S,5R)-N-{[(2R)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {(2R)-1-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-2-yl}carbamate,

tert-butyl {(2R)-1-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,

tert-butyl {(2R)-1-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}tetrabutylammonium carbamate,

(2S,5R)-N-{[(2S)-1-aminopropan-2-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {(2S)-2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate,

tert-butyl {(2S)-2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate,

tert-butyl {(2S)-2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}tetrabutylammonium carbamate,

(2S,5R)-N-(3-aminopropoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate,

tert-butyl {3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate,

tert-butyl {3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}tetrabutylammonium carbamate,

(2S,5R)-2-(1,2-oxazolidin-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one sodium,

(2S,5R)-6-benzyloxy-2-(1,2-oxazolidin-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octan-7-one,

(2S,5R)-6-hydroxy-2-(1,2-oxazolidin-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octan-7-one,

(2S,5R)-2-(1,2-oxazolidin-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one pyridinium,

(2S,5R)-2-(1,2-oxazinan-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one sodium,

(2S,5R)-6-benzyloxy-2-(1,2-oxazinan-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octan-7-one,

(2S,5R)-6-hydroxy-2-(1,2-oxazinan-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octan-7-one,

(2S,5R)-2-(1,2-oxazinan-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one pyridinium,

(2S,5R)-N-[2-(morpholin-4-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-N-[2-(morpholin-4-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-N-[2-(morpholin-4-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(morpholin-4-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carboxamide,

(2S,5R)-7-oxo-N-[2-(piperazin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl 4-{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}piperazine-1-carboxylate,

tert-butyl 4-{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}piperazine-1-carboxylate,

tert-butyl 4-{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}tetrabutylammonium piperazine-1-carboxylate,

(2S,5R)-7-oxo-N-[2-(1,4-diazepan-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl 4-{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1,4-diazepan-1-carboxylate,

tert-butyl 4-{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1,4-diazepan-1-carboxylate,

tert-butyl 4-{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1,4-diazepan-1-pyridinium carboxylate,

(2S,5R)-N-[(2S)-azetidin-2-ylmethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,

tert-butyl (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,

tert-butyl (2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-tetrabutylammonium carboxylate,

(2S,5R)-7-oxo-N-[(2S)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidin-1-carboxylate,

tert-butyl (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidin-1-carboxylate,

tert-butyl (2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyridinium-pyridinium-1-carboxylate,

(2S,5R)-7-oxo-N-[(2R)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl (2R)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidin-1-carboxylate,

tert-butyl (2R)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidin-1-carboxylate,

tert-butyl (2R)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}tetrabutylammonium pyrrolidine-1-carboxylate,

(2S,5R)-7-oxo-N-[(2S)-piperidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,

tert-butyl (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,

tert-butyl (2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-tetrabutylammonium carboxylate,

(2S,5R)-N-(azetidin-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl 3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate,

tert-butyl 3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate,

tert-Butyl-3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate tetrabutylammonium,

(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl (3R)-3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,

tert-butyl (3R)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,

tert-butyl (3R)-3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]tetrabutylammonium pyrrolidine-1-carboxylate,

(2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl (3S)-3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,

tert-butyl (3S)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,

tert-butyl (3S)-3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]tetrabutylammonium pyrrolidine-1-carboxylate,

(2S,5R)-N-(azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl 3-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,

tert-butyl 3-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,

tert-Butyl-3-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate tetrabutylammonium,

(2S,5R)-7-oxo-N-[(3R)-piperidin-3-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl (3R)-3-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,

tert-butyl (3R)-3-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,

tert-butyl (3R)-3-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-tetrabutylammonium carboxylate,

(2S,5R)-7-oxo-N-(piperidin-4-yloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-Butyl 4-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxamide,

tert-butyl 4-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate,

tert-Butyl 4-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate tetrabutylammonium,

(2S,5R)-7-oxo-N-(piperidin-4-ylmethoxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl 4-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,

tert-butyl 4-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,

tert-butyl 4-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate tetrabutylammonium,

(2S,5R)-N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carboxamide,

(2S,5R)-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carboxamide,

1-{2-[({[(2S,5R)-7-oxo-6-(sulfonoxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1H-imidazole-2-sulfonate disodium,

(2S,5R)-6-benzyloxy-N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

1-{2-[({[(2S,5R)-7-oxo-6-(sulfonoxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1H-imidazol-1-ium-2-pyridinium sulfonate,

(2S,5R)-N-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-N-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(dimethylamino)-2-oxoethoxy]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carboxamide,

(2S,5R)-7-oxo-N-[2-oxo-2-(piperazin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl 4-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}piperazine-1-carboxylate,

tert-butyl 4-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}piperazine-1-carboxylate,

tert-Butyl 4-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}tetrabutylammonium piperazine-1-carboxylate,

(2S,5R)-N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium,

(2S,5R)-N-[2-(1,4-diazepan-1-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl 4-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}-1,4-diazepan-1-carboxylate,

tert-butyl 4-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}-1,4-diazepan-1-carboxylate,

tert-butyl 4-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}-1,4-diazepan-1-carboxylate tetrabutylammonium,

(2S,5R)-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium,

(2S,5R)-7-oxo-N-[2-(2-oxoimidazolin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-7-oxo-N-[2-(2-oxoimidazolin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium,

(2S,5R)-N-(2-hydroxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-7-oxo-N-(2-triisopropylsilyloxyethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-7-oxo-N-(2-triisopropylsilyloxyethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-6-(sulfooxy)-N-(2-triisopropylsilyloxyethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide tetrabutylammonium,

(2S,5R)-N-(2-methoxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-N-(2-methoxyethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-N-(2-methoxyethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-(2-methoxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-pyridinium carboxamide,

(2S,5R)-N-[2-(methylsulfonyl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium,

(2S,5R)-6-benzyloxy-N-[2-(methylsulfonyl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-hydroxy-N-[2-(methylsulfonyl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(methylsulfonyl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium,

{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}benzyl carbamate, and

tert-butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate.

In addition, the following groups of compounds are preferably mentioned as specific examples of compounds according to the present invention.

in the above formulas, P ² is t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or H, P ³ is benzyl (Bn), H or SO ₃ M; where M is H, sodium, pyridinium or tetrabutylammonium.

in the above formulas, P ² is t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or H, P ³ is benzyl (Bn), H or SO ₃ M; where M is H, sodium, pyridinium or tetrabutylammonium and Ms is methylsulfonyl.

in the above formulas, P ² is t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or H, P ³ is benzyl (Bn), H or SO ₃ M; where M is H, sodium, pyridinium or tetrabutylammonium.

in the above formulas, P ² is t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or H, P ³ is benzyl (Bn), H or SO ₃ M; where M is H, sodium, pyridinium or tetrabutylammonium; and P ⁴ is triisopropylsilyl or H.

More preferably, specific examples include:

tert-butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,

tert-butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,

tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}pyridinium carbamate,

tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate sodium,

tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}tetrabutylammonium carbamate,

(2S,5R)-N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

benzyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,

(2S,5R)-N-[2-(methylamino)ethoxy]7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamate,

tert-butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamate,

tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}tetrabutylammonium methylcarbamate,

(2S,5R)-7-oxo-N-[2-(propan-2-ylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propan-2-ylcarbamate,

tert-butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propan-2-ylcarbamate,

tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}tetrabutylammonium propan-2-ylcarbamate,

(2S,5R)-N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-6-benzyloxy-N-[2-(dimethylamino)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(dimethylamino)ethoxy]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium,

(2S,5R)-N-{[(2S)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {(2S)-1-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,

tert-butyl {(2S)-1-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,

tert-butyl {(2S)-1-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}tetrabutylammonium carbamate,

(2S,5R)-N-{[(2R)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {(2R)-1-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,

tert-butyl {(2R)-1-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,

tert-butyl {(2R)-1-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}tetrabutylammonium carbamate,

(2S,5R)-N-(3-aminopropoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl {3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate,

tert-butyl {3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate,

tert-butyl {3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}tetrabutylammonium carbamate,

(2S,5R)-N-[(2S)-azetidin-2-ylmethoxy]7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,

tert-butyl (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,

tert-butyl (2S)-2{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-tetrabutylammonium carboxylate,

(2S,5R)-7-oxo-N-[(2R)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl (2R)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidin-1-carboxylate,

tert-butyl (2R)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidin-1-carboxylate,

tert-butyl (2R)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}tetrabutylammonium pyrrolidine-1-carboxylate,

(2S,5R)-7-oxo-N-[(2S)-piperidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,

tert-butyl (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,

tert-butyl (2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-tetrabutylammonium carboxylate,

(2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yloxy]6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl (3S)-3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,

tert-butyl (3S)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,

tert-butyl (3S)-3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]tetrabutylammonium pyrrolidine-1-carboxylate,

(2S,5R)-N-(azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

tert-butyl 3-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,

tert-butyl 3-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate, and

tert-butyl 3-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate tetrabutylammonium,

and the following groups of compounds.

in the above formulas, P ² is t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or H, P ³ is benzyl (Bn), H or SO ₃ M; where M is H, sodium, pyridinium or tetrabutylammonium.

Most preferably,

(2S,5R)-N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(methylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-N-[2-(propan-2-ylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-{[(2S)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-{[(2R)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-(3-aminopropoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-N-[(2S)-azetidin-2-ylmethoxy]7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-N-[(2R)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-N-[(2S)-piperidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,

(2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, and

(2S,5R)-N-(azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.

The medicament of the present invention contains a substance selected from the group consisting of a compound represented by formulas (I), (II) or (III) and a pharmaceutically acceptable salt thereof and a hydrate or solvate thereof as an effective ingredient, for oral or parenteral administration, and preferably parenteral administration. The compound of the present invention and the β-lactam antibiotic can be administered by a method in which separately prepared respective medicaments are administered simultaneously or separately in combination at the time of use, or by a method in which both medicaments are pre-mixed, usually with one or more drug additives (carriers), to obtain a pharmaceutical composition and to administer it.

Specific examples of pharmaceutical compositions for oral administration may include tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions.

Routes of administration for parenteral administration may include intranasal, eye drops, ear drops, subcutaneous, tracheobronchial, endorectal, urinary, subcutaneous, intramuscular, and intravenous.

Specific examples of pharmaceutical compositions for parenteral administration in the form of intravenous administration may include an injection solution for intravenous administration, for which the powder form of the pharmaceutical composition is dissolved in a suitable solvent. A suitable solvent includes, for example, sterile water for injection, saline, glucose solution, Ringer's solution, bacteriostatic water for injection containing methyl paraben and propyl paraben, or bacteriostatic water for injection containing benzyl alcohol.

The pharmaceutical composition in the form of a powder for parenteral administration can be obtained by sterilizing the compound of the present invention, which is an active ingredient, and a β-lactam antibiotic into a sealed vial and lyophilization, or by placing the pharmaceutical composition in a sterilized powder state into a sealed vial. Preferred specific sterilization methods include:

a method in which endotoxins are removed from individual or mixed solutions, insoluble substances are filtered, then crystallized, poured into a hermetically sealed vessel and irradiated with gamma rays;

a method in which endotoxins are removed from individual or mixed solutions, filtered under aseptic conditions, then sterilized, for example, by pressure steam sterilization and pulsed irradiation, and lyophilized;

a method in which endotoxins are removed from single or mixed solutions, filtered in an aseptic atmosphere, then filled into a sealed vial, frozen and covered, and then lyophilized;

a method in which endotoxins are separately removed from each compound solution, filtered under aseptic conditions, and crystallized in an aseptic atmosphere;

a method in which one of the aseptically crystallized sterilized powder drugs is applied in an aseptic atmosphere on top of another sterilized powder drug that is lyophilized in a sealed vial;

And

a method in which one of a drug in the form of a sterilized powder, lyophilized, and another drug in the form of a sterilized powder, crystallized in an aseptic atmosphere, are mixed in an aseptic atmosphere.

More preferred is a method in which endotoxins are removed from individual or mixed solutions, filtered under aseptic atmosphere, then filled into a sealed vial, frozen and coated, and then lyophilized, or a method in which endotoxins are separately removed from each solution of the compound, filtered under aseptic conditions and crystallized in an aseptic atmosphere.

The above pharmaceutical composition can be stored at or below room temperature until an intravenous solution is obtained from it, it is dissolved immediately before use. The concentration of the compound according to the invention in the reconstituted intravenous solution is, for example, 1 mg/ml to 50 mg/ml.

The administration dose and the number of administrations of the pharmaceutical composition according to the present invention is not particularly limited, and the administration dose and the number of administrations are optionally determined depending on various conditions such as therapeutic or prophylactic purposes, disease type, age, body weight, and symptoms of the patient. The effective blood concentration of a compound of this invention for use in combination with β-lactam antibiotics is adjusted to be 1 μg/ml or more during administration of the β-lactam antibiotic. The dose of the compound according to the present invention for intravenous administration is preferably 2 to 75 mg/kg per dose, and for oral administration is preferably 4 to 300 mg/kg several times a day depending on the number of administrations of the β-lactam antibiotic, which is preferably 2 to 6 times.

The β-lactam antibiotic that can be used in combination with the compound of this invention includes penicillin, cefem and carbapenem.

Specific examples of penicillins include benzylpenicillin, pheneticillin, cloxacillin, dicloxacillin, ampicillin, cyclacillin, amoxicillin, thalampicillin, becampicillin, lenampicillin, aspoxicillin, piperacillin, sulbenicillin, pivmecillinam, sultamicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, epicillin, ticarcillin, pirbenicillin, azlocillin, mezlocillin and other known penicillins.

Specific examples of cephems include cefaclor, cefazolin, cefatrizin, cefadroxil, cefapirin, cefamandole naphate, cephadrin, cefalexin, cefalotin, cefepime, cefoxitin, cefixime, ceftazidime, cefditoren, cefdinir, cefsulodine, cefoselis, cefozoprane, cefotaxime, ceftazidime, ceftaroline, cefotiam, ceftizoxime, ceftibuten, ceftezol, cefteram, ceftriaxone, cefonicide, cefpiramide, cefpirome, cefbuperazone, cefprozil, cefoperazone, cefpodoxime, cefminox, cefmetazole, cefmenoxime , cephradine, cefroxadine, cefuroxime, ceftolosan (CXA101, (6R,7R)-3-[5-amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1 hydrogensulfate -carboxy-1-methylethoxyimino]acetamide]-3-cephem-4-carboxylic acid) and other known cephems.

Examples of carbapenems include imipenem, panipenem, meropenem, biapenem, doripenem, ertapenem and tebipenem, and a DHP-1 inhibitor such as cilastatin can be used in combination with them as needed.

Examples of β-lactam antibiotics other than carbapenems, penicillins and cephems include β-lactam antibiotics such as aztreonam, carumonam, latamoxef, flomoxef, loracarbef, faropenem and ritipenem.

Examples of penicillins particularly suitable for use in combination with a compound of this invention include ampicillin, amoxicillin, carbenicillin, piperacillin, azlocillin, mezlocillin and ticarcillin. Such penicillins can be used, for example, in the form of pharmaceutically acceptable salts such as sodium salts. Alternatively, ampicillin or amoxicillin may be used in combination with a compound of formula (I) in the form of an injection suspension or in the form of fine particles of an amphoteric ion (ampicillin trihydrate or amoxicillin trihydrate) for an injection suspension.

Particularly preferred cephemes for co-administration with a compound of this invention include cefotaxime, ceftriaxone, ceftazidime, cefepime, etc., and may be used in the form of a pharmaceutically acceptable salt such as the sodium salt.

Particularly suitable carbapenems for co-administration with a compound of this invention include imipenem, meropenem, biapenem, doripenem and ertapenem.

An example of a particularly suitable β-lactam antibiotic for co-administration with a compound of the present invention is aztreonam.

The use of a compound according to the invention and a β-lactam antibiotic in combination can be used to treat infection caused by class A and class C β-lactamase producing strains and ESBL and KPC2 carbapenemase producing strains, in addition to bacterial infection included in the antimicrobial spectrum of antibiotics.

Class A and class C β-lactamase producing strains and ESBL and KPC2 carbapenemase producing strains include Escherichia coli, Klebsiella pneumoniae, Enterobacter croacare, Citrobacter freundii, Serratia marcescens, Morganella morganii, Pseudomonas aeruginosa and Acinetobacter baumannii .

The following explains in more detail the general method for obtaining the present compound.

The compounds used to study and evaluate the present invention can be synthesized using a side chain forming compound (A-BH) and a carboxylic acid represented by formula (6b) according to Scheme 1:

Scheme 1

in the diagram above, OBn is benzyloxy,

including the method described in US Pat. No. 7,112,592 by modifying and improving the reaction conditions, post-processing step, and purification step, taking into account the reactivity of the respective functional groups or the stability characteristic of the respective compounds.

That is, the optically active carboxylic acid of the formula (6b) and the side chain-forming compound (A-BH) are treated by a method selected from a mixed acid anhydride method, an active esterification method, an active amidation method, or a condensing agent dehydration method in the presence of a base to obtain a compound represented by the formula (Ia), benzyl from the benzyloxy of the formula (Ia) is subjected to a hydrogenolysis reaction in a hydrogen atmosphere in the presence of a catalyst selected from platinum oxide, palladium oxide, palladium black and palladium on charcoal and optionally in the presence of di-tert-butoxydicarbonate to give a compound represented by formula (Ib), the hydroxyl group of formula (Ib) is sulfonated with a sulfating agent selected from sulfur trioxide-pyridine complex, sulfur trioxide-dimethylformamide complex and chlorosulfonic acid in the presence of a base selected from pyridine, 2-picoline and 2,6 -lutidine and 2,4,6-collidine to give the compound represented by formula (Ic) and optionally the protecting group is treated with an amino group (e.g., tert-butoxycarbonyl group (Boc)), if necessary, the protective group is treated with an acid (e.g., selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid) or tetrafluoroboric acid, etc.) to deprotect, and then, the compound represented by formula (Id) is purified with octadecyl by silica gel column chromatography, synthetic resin column chromatography such as DIAION HP21 (from Mitsubishi Chemical Corporation), SEPABEADS SP207 (from Mitsubishi Chemical Corporation) or preparative HPLC, etc. at a suitable pH, etc., to give the desired compound.

The optically active carboxylic acid represented by formula (6b) can be synthesized according to the following Scheme 2:

Scheme 2

in the above scheme, Cbz is benzyloxycarbonyl, t-Bu is tert-butyl, ATPA is trifluoroacetic anhydride, TFA associated with compound is trifluoroacetyl, Tf ₂ O is trifluoromethanesulfonic anhydride, Bn ₂ ONH is benzyloxyamine, DMAP is 4-dimethylaminopyridine, TFA separately described in the diagram is trifluoroacetic acid , OBn is benzyloxy and LiOH is lithium hydroxide,

and the methods are presented in the Examples of the present invention.

That is, benzyloxycarbonyl from a known compound represented by formula (1) is removed by a hydrogenolysis reaction in the presence of a catalyst such as palladium-carbon under a hydrogen atmosphere to obtain a compound represented by formula (2); converting it by reacting with trifluoroacetic anhydride in the presence of triethylamine to obtain a compound represented by formula (3); reacting its hydroxyl group at position 5 with trifluoromethanesulfonic acid anhydride in the presence of 2,6-lutidine, then with benzyloxyamine to obtain a compound represented by formula (IV); removal of trifluoroacetyl using sodium hydroxide to obtain a compound represented by formula (4a), or removal of trifluoroacetyl using hydrochloride-methanol and an ester exchange reaction simultaneously to obtain a compound represented by formula (4b); their interaction with diphosgene or phosgene in the presence of triethylamine or 4-dimethylaminopyridine to obtain a compound represented by formula (5a) or (5b); and ester cleavage at the 2-position by acid treatment using trifluoroacetic acid, and so on. or by treatment with a base using lithium hydroxide, etc., to obtain (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid represented by formula (6b). Or else, commercially available (2S,5S)-5-hydroxypiperidine-2-carboxylic acid represented by formula (7) or its hydrochloride is converted into a compound represented by formula (10) or (4b) by the method described above without purification, and isolated as a hydrochloride, then (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic oic acid represented by formula (6b).

From the side chain compounds A-BH, the particular hydrazine derivative represented by Ra(Rb)N-BH can be synthesized according to Scheme 3 below:

Scheme 3

in the above scheme, Cbz represents benzyloxycarbonyl.

That is, it can be easily synthesized by reacting an ester and hydrazine monohydrate, amidating an acid chloride and N-benzyloxycarbonyl hydrazine in the presence of a suitable base, or amidating a carboxylic acid and N-benzyloxycarbonyl hydrazine using a dehydrating condensing agent or a mixed acid anhydride method, followed by hydrogenolysis of the benzyloxycarbonyl group in the presence of a catalyst such as palladium on corner.

In addition, a specific alkoxyamine represented by RcOBH is synthesized by the method shown in the following Scheme 4:

Scheme 4

That is, it can be easily synthesized by combining N-hydroxyphthalimide and a suitable alcohol derivative using the Mitsunobu reaction, or by reacting with an alkylating agent having a leaving group such as an alkyl halide and a methylsulfonyloxy group, followed by deprotection of the phthalimide with an organic base such as hydrazine monohydrate or methylamine.

The following is a more detailed description of a method for producing a compound represented by the following formula (III):

in the above formula (III), Rc is C _1-6 alkyl or heterocyclyl; B is NH or NC _1-6 alkyl; M is H, an inorganic cation or an organic cation; Rc may be modified with 0 to 4 Fn1 substituents, where the Fn1 substituent may be further substituted; Fn1 is C _1-6 alkyl, O= or Rg-(CH ₂ ) _0-3- , where Rg is heterocyclyl, phenyl, heteroaryl, acyl, RdO ₂ S-, Re(Rf)N-, Re(Rf)NCO-, ReO-, ReOCO- or a protecting group, where Rd is C _1-6 alkyl or MO-; Re and Rf are each independently H or C _1-6 alkyl; and between Rc and B and between Re and Rf can be closed by bonding to give a heterocyclyl having at least one nitrogen atom,

presented in this invention.

In the production method according to the present invention, as a suitable protecting group represented by P ¹ in the starting material represented by the following formula (IV-a):

in the above formula (IV-a), P ¹ is a protective group that can be removed with an acid, a base, or a nucleophilic agent; and OBn is benzyloxy,

an amino acid protecting group that can be removed with an acid, base, or nucleophilic agent can be used, as described in Protective Groups in Organic Synthesis (T. W. Greene et al., Wiley, New York (1999)). More specifically, it includes tert-butoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 1,1-dimethylpropynyloxycarbonyl, 1-methyl-1-(4-biphenylyl)ethoxycarbonyl, 1-methylcyclobutoxycarbonyl, 1-adamantyloxycarbonyl, diphenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl, 1,1-dimethyl-2-cyanoethoxycarbonyl yl, formyl, trichloroacetyl, trifluoroacetyl, benzenesulphenyl, 2-nitrobenzenesulphenyl, 2-trimethylsilylethanesulfonyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl, 2-naphthalenesulfonyl, 9-anthracenesulfonyl and benzenethiazolesulfonyl, preferably tert-butoxycarbonyl , 2-trimethylsilylethoxycarbonyl, trifluoroacetyl, 9-fluorenylmethoxycarbonyl, 2-nitrobenzenesulfonyl, and 4-nitrobenzenesulfonyl.

A step for obtaining a compound represented by the following formula (IV-b):

in the above formula (IV-b), P ¹ is a protective group that can be removed with an acid, a base, or a nucleophilic agent; Rc and B are as defined for the compound represented by formula (III), and OBn is benzyloxy,

comprising the combination of a compound represented by formula (IV-a) with a side chain-forming compound: RcOBH can be carried out by a method in which the compound represented by formula (IV-a) is treated with an active ester, an active amide or a dehydrating condensing agent in a suitable solvent.

The coupling using a dehydrating condensing agent is carried out in many cases by adding an active ester group or an active amide group as a catalyst to obtain an active ester or an active amide in the reaction system, and specific examples are presented and explained below.

The solvent used for the dehydrating condensing agent is water, methanol, ethanol, isopropanol, ethyl acetate, toluene, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, etc., preferably ethyl acetate, tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, dimethylacetamide, which can be used alone or in admixture.

If an active esterifying agent or an active amidating agent is used, the reaction is carried out in the presence of a base, if necessary. The base used in this reaction is triethylamine, diisopropylethylamine, tributylamine, N-methylmorpholine and 4-dimethylaminopyridine, preferably triethylamine, and is used in an amount of 1 to 3 equivalents, depending on the compound represented by formula (IV-a), preferably 1 to 1.5 equivalents.

As a dehydrating condensing agent, a carbodiimide such as N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride can be used alone, or in combination with an active amide or ester group such as imidazole, 1-hydroxybenzotriazole monohydrate, N-hydroxysuccinimide and 2-hydroxypyr idine-N-oxide, as well as an active esterifying agent or an active amidating agent such as carbonyldiimidazole, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 2-chloro-1-methylpyridinium iodide and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, preferably hydrochloride 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide in combination with 1-hydroxybenzotriazole monohydrate, or the selected 2-chloro-1-methylpyridinium iodide, and the agent is used in the range of 1.0 to 2.0 equivalents with respect to the compound represented by formula (IV-a), more preferably 1.0 to 1.5 equivalents. The reaction temperature is -40°C to room temperature, preferably -20°C to room temperature. The reaction is carried out for 30 minutes to 1 day, preferably 2 hours to 16 hours.

The compound represented by formula (IV-b) can be isolated by diluting the reaction mixture with an appropriate solvent after completion of the reaction, successively washing with water, dilute acid, an aqueous base solution (for example, dilute hydrochloric acid, potassium monohydrosulfate, citric acid, or aqueous sodium bicarbonate, saturated saline), and evaporating the solvent to the concentration of the reaction mixture. The organic solvent used for dilution is diethyl ether, ethyl acetate, butyl acetate, toluene, dichloromethane and chloroform, preferably ethyl acetate.

Then, the step of deprotecting the compound represented by the above formula (IV-b) to obtain the compound represented by formula (IV-c):

in the above formula (IV-c), Rc and B are as defined for the compound represented by formula (III), and OBn is benzyloxy,

can be carried out as follows.

The solvent used in the deprotection under acidic conditions is water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane and 2,2,2-trifluoroethanol, etc., preferably water, methanol, ethanol, ethyl acetate, dioxane and dichloromethane, which can be used alone or in combination.

The acid used in acidic deprotection is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, chloromethanesulfonic acid, tetrafluoroboric acid, etc., preferably hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and tetrafluoroboric acid, more preferably hydrochloric acid acid or trifluoroacetic acid. The acid is used in an amount of 1 equivalent to the amount of the solvent, with respect to the compound represented by the formula (IV-b), preferably 5 times the amount of the solvent. The reaction temperature is -25°C to 50°C, preferably -10°C to 30°C. The reaction is carried out for 30 minutes to 16 hours, preferably 30 minutes to 5 hours.

The solvent used in the deprotection under alkaline conditions or using a nucleophilic agent is water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, and 2,2,2-trifluoroethanol, etc., preferably water, methanol, tetrahydrofuran and dioxane, which can be used alone or in combination.

The base used in alkaline deprotection is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably lithium hydroxide, sodium hydroxide and potassium hydroxide, and is used in an amount of 2 to 5 equivalents with respect to the compound represented by formula (IV-b), preferably in an amount of 2 to 4 equivalents. The reaction temperature is in the range from -25°C to 50°C, preferably from 0°C to 10°C. The reaction is carried out for 30 minutes to 16 hours, preferably 30 minutes to 5 hours.

The nucleophilic agent used in deprotection using a nucleophilic agent is a thiol such as ethanethiol, thioglycolic acid and thiophenol; and a fluoride such as pyridine hydrofluoride, sodium fluoride, potassium fluoride, cesium fluoride and tetrabutylammonium fluoride, preferably tetrabutylammonium fluoride, and it is used in an amount of 2 to 4 equivalents with respect to the compound represented by formula (IV-b), preferably 2 to 3 equivalents. The reaction temperature is in the range of 0°C to 100°C, preferably 25°C to 60°C. The reaction is carried out for 2 hours to 48 hours, preferably 8 hours to 24 hours.

The compound represented by formula (IV-c) having an RcONHCO group with weak acid properties is an amphoteric substance so as to obtain an optimal pH range for obtaining the compound as a free base. The optimum pH is between PH6 and 9, preferably between pH6 and 8.

The compound represented by formula (IV-c) can be isolated by diluting the reaction mixture with an organic solvent, adjusting to the optimum pH as above, and extracting with a solvent. The organic solvent used to dilute the alkaline reaction mixture is diethyl ether, ethyl acetate, butyl acetate, toluene, dichloromethane and chloroform, preferably ethyl acetate or dichloromethane.

Then, a step of silylation of a compound represented by formula (IV-c) in an intramolecular urea continuous reaction system to obtain a compound represented by the following formula (IIa):

in the above formula (IIa), Rc and B are as defined for the compound represented by formula (III), and OBn is benzyloxy,

can be carried out as follows.

The solvent used in the reaction may be ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, etc., preferably acetonitrile.

The base used in this reaction is triethylamine, diisopropylethylamine, tributylamine, N-methylmorpholine, preferably triethylamine, and is used in an amount of 3 to 6 equivalents with respect to the compound represented by formula (IV-c), preferably 3 to 4 equivalents.

The silylating agent used in the reaction is chlorotrialkylsilane such as chlorotrimethylsilane, chlorotriethylsilane, chlorotriisopropylsilane and chloro-t-butyldimethylsilane; trimethylsilyl trifluoromethanesulfonate and tert-butyldimethylsilyl trifluoromethanesulfonate, preferably chlorotrialkylsilane such as chlorotrimethylsilane, and used in an amount of 1 to 3 equivalents with respect to the compound represented by formula (IV-c), preferably 1 to 1.5 equivalents.

The urea forming agent used in the reaction is phosgene, diphosgene, triphosgene and carbonyldiimidazole, and preferably phosgene and diphosgene, and is used in an amount of 0.5 to 2 equivalents with respect to the compound represented by formula (IV-c), preferably 0.5 to 1.0 equivalents. Simultaneously, to complete the formation of urea, a catalytic amount of 4-dimethylaminopyridine is used in an amount of 0.1 to 1 equivalent with respect to the compound of formula (IV-c), preferably 0.1 to 0.2 equivalent.

The reaction temperature is -25 to 50°C, preferably -15 to 30°C. The reaction is carried out for 10 minutes to 24 hours, preferably 1 hour to 16 hours.

The resulting compound represented by formula (V-2) can be isolated by conventional post-treatment such as evaporating the organic solvent in the reaction mixture at its concentration, diluting with the solvent, washing with acid and base, evaporating the solvent at the concentration of the mixture, and precipitating.

Then, the step of obtaining a compound represented by the following formula (IIb):

in the above formula (IIb), Rc and B have the meanings defined for the compound represented by formula (III),

Cleavage of the benzyl group from the benzyloxy group at the 6-position of the compound represented by the above formula (IIa) using a hydrogenolysis catalyst under a hydrogen atmosphere is carried out as follows.

The solvent used in this reaction is water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran and dioxane, preferably methanol or tetrahydrofuran, which are used alone or in combination.

The hydrogenolysis catalyst is platinum oxide, palladium hydroxide, palladium black or palladium on charcoal, preferably palladium on charcoal.

The catalyst is used in an amount of 5 to 100% by weight relative to the compound of formula (IIa), preferably 5 to 30% by weight.

The hydrogen source used for hydrogenolysis is hydrogen gas, and the hydrogen pressure is selected in the range of atmospheric pressure to 1 MPa, preferably atmospheric pressure to 0.5 MPa. Alternatively, the hydrogen source may be ammonium formate, cyclohexene, or cyclohexadiene. The amount of hydrogen used may be at least a stoichiometric amount.

The hydrogenolysis reaction temperature is 10 to 50°C, preferably 15 to 30°C. The reaction is carried out for 0.5 to 3 hours, preferably 0.5 to 2 hours.

If an amino group and a benzyloxycarbonyl group are present as a protecting group in the Rc side chain of the compound represented by formula (IIa), they can be protected again with a t-butoxycarbonyl group in the presence of di-t-butoxycarbonyl dicarbonate in the above hydrogenolysis reaction.

The amount of di-tert-butoxycarbonyl dicarbonate added is 1 to 2 equivalents, relative to the compound of formula (IIa), preferably 1 to 1.2 equivalents. After completion of the reaction, the compound represented by the formula (IIb) can be isolated by conventional methods such as filtering the catalyst and evaporating the solvent to concentrate the mixture.

Then, the step of obtaining the compound represented by the above formula (III) by sulfating the hydroxyl group at the 6-position of the compound represented by formula (IIb) in the presence of a base, and deprotecting the side chain protecting group (RcO) if necessary, can be carried out as follows.

The solvent used for sulfation may be water, methanol, ethanol, isopropanol, dichloromethane, chloroform, 1,2-dichloroethane, pyridine, acetonitrile and dimethylformamide, preferably dichloromethane, pyridine and acetonitrile, which are used alone or in combination.

The base used in this reaction may be triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 2-picoline, 3-picoline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopiperidine and N-methylimidazole, preferably pyridine, 2-picoline and 2,6-lutidine, and is used in the amount 1.0 to the amount of solvent, with respect to the compound represented by formula (IIb), preferably 3.0 to the amount of solvent.

The product used as the sulfating agent is chlorosulfonic acid, sulfur trioxide-pyridine complex, sulfur trioxide-dimethylformamide complex, sulfur trioxide-trimethylamine complex and sulfur trioxide-triethylamine complex, preferably sulfur trioxide-pyridine complex or sulfur trioxide-dimethylformamide complex, and is used in an amount of 1 to 4 equivalents based on the compound represented by formula (IIb), preferably 2 up to 3 equivalents. The reaction temperature is 0 to 50°C, preferably 10 to 30°C. The reaction is carried out for 12 to 48 hours, preferably for 12 to 24 hours.

After completion of the reaction, the compound represented by the formula (III) can be obtained as a pyridinium salt of sulfonic acid by filtration and evaporation of the solvent at the concentration of the reaction mixture, and treatment with an aqueous solution of an inorganic base containing sodium, such as an aqueous solution of sodium bicarbonate, to obtain a sodium salt, adding 1 to 3 molar equivalents of tetrabutylammonium hydrogen sulfate to an aqueous solution of sodium salt, and extracting with an organic solvent such as ethyl acetate to obtain a tetrabutylammonium salt, and the above aqueous solution is adjusted to the optimum pH to obtain an intramolecular salt for use in the next step, or the product is purified to obtain a compound represented by formula (III) as the final form.

Here, the optimum pH is the pH range in which the compound represented by formula (III) can stably exist as an intramolecular salt. A pH range of 4 to 7 is chosen to isolate the compound as an intramolecular salt, more preferably a pH of 5 to 6.

If a protecting group (eg tert-butoxycarbonyl group) is present on the side chain (RcO) of formula (III), it is also used in the deprotection step.

To deprotect the tert-butoxycarbonyl group on the side chain (RcO), deprotection under acidic conditions is used.

The solvent used for the reaction is water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, 2,2,2-trifluoroethanol, etc., preferably dichloromethane, ethyl acetate or 2,2,2-trifluoroethanol.

The acid used in the deprotection under acidic conditions is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, chloromethanesulfonic acid, tetrafluoroboric acid, etc., preferably hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and tetrafluoroboric acid. More preferably, hydrochloric acid, sulfuric acid and trifluoroacetic acid. The acid is used in an amount of 1 equivalent to the amount of solvent relative to the compound of formula (III), preferably 3 times the amount of solvent. The reaction temperature is -25 to 50°C, preferably -10 to 30°C. The reaction is carried out for 30 minutes to 5 hours, preferably 30 minutes to 1 hour.

After deprotection is completed, the solvent of the reaction mixture is evaporated to the concentration of the mixture, or a weak solvent is added to precipitate the crude product and then the mixture is diluted to an aqueous solution with an optimal pH in the range of pH5 to 6 and then precipitated again, or purified using octadecyl-silica (SOD), a synthetic polymer such as Diaion HP-20 and Sepabeads SP207, and ion exchange resins s, such as DOWEX 50W-X8 (Na form), followed by precipitation or lyophilization to obtain the compound represented by formula (III) in the final form.

The following explains in detail the method for precipitating the compound represented by the above formula (III) and (2S,5R)-7-oxo-N-(2-aminoethoxy)-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide represented by the formula (III-059):

The step of obtaining (2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate represented by the above formula (4b) or its hydrochloride can be carried out as follows.

Methyl esterification of commercially available (2S,5S)-5-hydroxypiperidine-2-carboxylic acid represented by formula (7) or its hydrochloride is carried out in methanol with heating in the presence of a suitable acid. The acid used is hydrogen chloride, sulfuric acid, perchloric acid, methanesulfonic acid, p-toluenesulfonic acid, preferably hydrogen chloride. When hydrogen chloride is used, it is used in an amount of 3 to 6 equivalents, preferably 4 to 5 equivalents, based on the molar number/mass ratio obtained from the consumed amount of acid/base of the compound represented by formula (7). The reaction is carried out at the boil under reflux for 2 to 4 hours, preferably 3 hours. After completion of the reaction, the residue obtained by concentrating the reaction mixture was made basic and extracted with a suitable organic solvent to isolate (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate represented by formula (8). The base used may be sodium hydroxide, sodium carbonate and potassium carbonate, preferably potassium carbonate. The solvent used for the extraction may be diethyl ether, ethyl acetate, dichloromethane, chloroform, preferably ethyl acetate. The isolated compound represented by formula (8) can be used in the next step without further purification.

Trifluoroacetylation of (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate represented by formula (8) is carried out by reaction with trifluoroacetic anhydride in the presence of triethylamine. Trifluoroacetic anhydride is used in an amount of 0.9 to 1.3 equivalents, preferably 1.0 equivalents, based on the sum of the molar number/mass ratio of the compound represented by formula (8) obtained by the prelabeled HPLC method and the molar number/mass ratio obtained from the amount of acid consumed. In addition, triethylamine is used in an amount twice that of trifluoroacetic anhydride. The reaction solvent is selected from dichloromethane, chloroform, dichloroethane, ethyl acetate and tetrahydrofuran, preferably ethyl acetate. The reaction is carried out at -70°C to 0°C, preferably -40°C to 0°C, and the reaction time is 60 to 120 minutes, preferably 60 to 90 minutes. (2S,5S)-methyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate represented by formula (9) is isolated by adding water to the reaction mixture to hydrolyze the trifluoroacetoxy group at position 5 only, followed by washing with ordinary acid/base and concentrating the mixture under reduced pressure. The isolated compound represented by formula (9) can be used in the next step without further purification.

The step of benzyloxyamination of the hydroxyl group at position 5 of (2S,5S)-methyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate represented by formula (9) may be carried out by reacting with trifluoromethanesulfonic acid anhydride in an amount of 1 to 1.1 equivalents, preferably one equivalent, in the presence of 2,6-lutidine in an amount of 1 to 1.2 equivalents and preferably 1.1 equivalents with respect to the HPLC titer of the compound represented by formula (9) in a reaction system to obtain a trifluoromethanesulfonic acid ester, then reacting the obtained compound with benzyloxyamine in an amount of 1 to 3 equivalents, preferably 2 equivalents, in the presence of 2,6-lutidine in an amount of 1 to 1.2 equivalents, preferably 1.1 equivalents. The reaction solvent is selected from dichloromethane, chloroform, 1,2-dichloromethane, tetrahydrofuran and acetonitrile, preferably acetonitrile. The reaction is carried out at -50°C to 50°C, preferably -35°C to 0°C, and the reaction time is 1 to 5 days, preferably 2 to 3 days. (2S,5R)-methyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate represented by formula (10) can be isolated and purified by concentrating the reaction mixture under reduced pressure, diluting the residue with a solvent such as ethyl acetate, etc., washing with an ordinary acid/base, and concentrating the mixture under reduced pressure to obtain the crude compound represented by formula (10), then dissolving the crude product in ethyl acetate and adding a hydrogen chloride-ethyl acetate solution to obtain a hydrochloride of the compound represented by formula (10).

Removal of the 2,2,2-trifluoroacetyl group of (2S,5R)-methyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate represented by formula (10) can be carried out in methanol with heating in the presence of a suitable acid. The acid used is hydrogen chloride, sulfuric acid, perchloric acid, methanesulfonic acid and p-toluenesulfonic acid, preferably hydrogen chloride. The amount of hydrogen chloride used is 10 to 20 equivalents, preferably 13 to 18 equivalents, with respect to the compound represented by formula (10). The reaction time is 1 to 4 days, preferably 1 to 3 days. When using an acid other than hydrogen chloride, the residue obtained by concentrating the reaction mixture under reduced pressure is made basic, (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylate free base represented by formula (4b) is extracted once with a suitable organic solvent, and then an acid selected from oxalic acid and hydrogen chloride is added to isolate and purify the target compound as a salt. In the case of using hydrogen chloride, the reaction mixture is concentrated, and ethyl acetate is added as a weak solvent to isolate and purify the hydrochloride of the compound represented by formula (4b).

Here, the compound represented by the formula (4b) can be easily isolated and purified as a hydrochloride by crystallization so as to obtain an intermediate highly advantageous industrially.

A compound represented by the following formula (IV-a2), (IV-a3) or (IV-a4):

in the above formula IV-a2), (IV-a3) or (IV-a4) TFA is trifluoroacetyl, Boc is t-butoxycarbonyl, Teos is 2-trimethylsilylethoxycarbonyl and OBn is benzyloxy,

can be obtained by the following scheme 5:

Scheme 5

in the above scheme, free TFA is trifluoroacetic acid, TFA associated with the chemical formula is trifluoroacetyl, t-Bu is t-butyl, OBn is benzyloxy, Boc ₂ O is di-t-butoxydicarbonate, TeocO-Su is N-(2-trimethylsilylethoxycarbonyloxy)succinimide, Boc is t-butoxycarbonyl and Teos is 2-trimethyl silylethoxycarbonyl,

from the compound represented by formula (IV) or (4b) in Synthesis Scheme 2 of optically active carboxylic acid (6b) by the method shown in the examples.

That is, the compound represented by formula (IV-a2) can be obtained by cleaving the t-butoxy ester of the compound represented by formula (IV) with enough trifluoroacetic acid to dissolve in a halogen serial solvent such as dichloromethane or chloroform.

Also, the compound represented by formula (IV-a1) can be obtained by removing trifluoroacetyl from the compound represented by formula (IV) with a base selected from sodium hydroxide and potassium hydroxide in hydrogenated dioxane, cleaving tert-butoxy ester with an acid selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid or methanesulfonic acid to obtain a compound represented by formula (IV-a1), which can be used in the next step after isolation. or no selection. In addition, the hydrochloride methyl ester of the compound represented by formula (4b) is cleaved off under the same basic conditions to obtain a solution of the compound represented by formula (IV-a1), and the compound can be used in the next step without purification.

The compounds represented by formulas (IV-a3) and (IV-a4) can be obtained by dissolving the compound represented by formula (IV-a1) in aqueous dioxane or aqueous tetrahydrofuran and reacting with a t-butoxycarbonylating agent selected from Boc ₂ O (di-t-butoxydicarbonate), Boc-ON (2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile) and Boc -OSu (N-(tert-butoxycarbonyloxy)succinimide), or with N-(2-trimethylsilylethoxycarbonyloxy)succinimide in the presence of a base selected from sodium hydroxide, sodium carbonate and triethylamine.

(2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylic acid,

(2S,5R)-5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylic acid,

(2S,5R)-5-(benzyloxyamino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid, and

(2S,5R)-5-(benzyloxyamino)-1-((2-(trimethylsilyl)ethoxy)carbonyl)piperidine-2-carboxylic acid,

which have formulas (IV-a1), (IV-a2), (IV-a3) and (IV-a4), respectively, in Scheme 5 above, are new compounds, and they are useful not only in the field of the present invention, but also as general starting materials.

In said formulas (IV-a2), (IV-a3) and (IV-a4), the step of obtaining a compound represented by the following formula (IV-b2-Boc-059), (IV-b3-Cbz-059), (IV-b4-Boc-059):

in the above formulas (IV-b2-Boc-059), (IV-b3-Cbz-059), (IV-b4-Boc-059), TFA is trifluoroacetyl, Boc is t-butoxycarbonyl, Cbz is benzyloxycarbonyl, Teos is 2-trimethylsilylethoxycarbonyl, and OBn is benzyloxy,

the combination of the compounds represented by formulas (IV-a2) and (IV-a4) by the method using tert-butyl 2-(aminooxy)ethylcarbamate and the active ester, the active amide or the dehydrating condensing agent, and the combination of the compound represented by the formula (IV-a3) by the method using benzyl 2-(aminooxy)ethylcarbamate and the active ester, the active amide or the dehydrating condensing agent is carried out as follows.

The amount of tert-butyl 2-(aminooxy)ethylcarbamate or benzyl 2-(aminooxy)ethylcarbamate is 1 to 2 equivalents with respect to the compound represented by formula (IV-a2), (IV-a3) or (IV-a4), preferably 1.0 to 1.5 equivalents.

The coupling using a dehydrating condensing agent is carried out in many cases by adding an active ester group or an active amide group as a catalyst to obtain an active ester or an active amide in the reaction system, specific examples are presented and explained below.

When using a dehydrating condensing agent, a solvent selected from ethyl acetate, toluene, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, etc. is used, and preferably ethyl acetate, tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, and dimethylacetamide.

When using an active esterifying agent as the active amidating agent, the reaction is carried out in the presence of a base, if necessary. The base used in this reaction includes triethylamine, diisopropylethylamine, tributylamine, N-methylmorpholine and 4-dimethylaminopyridine, preferably triethylamine, and is used in an amount of 1 to 3 equivalents with respect to the compound represented by the formula (IV-b2-Boc-059), (IV-b3-Cbz-059), (IV-b4-Boc-059), if necessary, preferably from 1 to 1.5 equivalents.

As a dehydrating condensing agent, only a carbodiimide such as N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride can be used, or in combination with an active ester group such as 1-hydroxybenzotriazole monohydrate, N-hydroxysuccinimide and 2-hydroxypyridine-N-oxide, and also an active amidating agent or an active esterifying agent such as carbonyldiimidazole, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, 2-chloro-1-methylpyridinium iodide and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, preferably 1-ethyl-3-(3-dimethylamino) hydrochloride propyl)carbodiimide in combination with 1-hydroxybenzotriazole monohydrate, or the selected 2-chloro-1-methylpyridinium iodide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are used in an amount of 1 to 2 equivalents and 1-hydroxybenzotriazole monohydrate in an amount of 1 to 2 equivalents, relative to the compound represented by formula (IV-a2), (IV-a3) or ( IV-a4), preferably 1 to 1.3 equivalents of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.1 to 0.3 equivalents of 1-hydroxybenzotriazole monohydrate. The reaction temperature is -40°C to room temperature, preferably -20°C to room temperature. The reaction is carried out for 30 minutes to 1 day, preferably 2 hours to 16 hours.

The compound of formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or (IV-b4-Boc-059) which is the coupling product can be isolated after completion of the reaction by diluting the reaction mixture with a suitable solvent, successively washing with water, dilute acid, aqueous alkaline solution (for example, dilute hydrochloric acid, potassium monohydrogen sulfate, citric acid, or aqueous bicarbonate solution). sodium) and evaporation of the solvent with the concentration of the reaction mixture. The organic solvent used for dilution may be diethyl ether, ethyl acetate, butyl acetate, toluene, dichloromethane and chloroform, preferably ethyl acetate.

Then, a step of removing the trifluoroacetyl group of the compound represented by the above formula (IV-b2-Boc-059) by treatment with a base to obtain a compound represented by the following formula (IV-c-Boc-059):

in the above formulas (IV-c-Boc-059) or (IV-c-Cbz-059), Boc is t-butoxycarbonyl, Cbz is benzyloxycarbonyl and OBn is benzyloxy,

carried out as follows.

The solvent used to remove the trifluoroacetyl group is water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, etc., preferably water, methanol, tetrahydrofuran and dioxane, which can be used alone or in combination, more preferably aqueous dioxane or tetrahydrofuran.

The base is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably lithium hydroxide, sodium hydroxide and potassium hydroxide, more preferably sodium hydroxide, and is used in an amount of 2 to 4 equivalents with respect to the compound represented by formula (IV-b2), preferably 2 to 3 equivalents.

The reaction temperature is -20°C to 30°C, preferably 0 to 10°C. The reaction time is 1 to 16 hours, preferably 1 to 3 hours.

The compound represented by the formula (IV-c-Boc-059) having the RcONHCO group, which exhibits the properties of a weak acid, is an amphoteric substance so as to obtain an optimal pH range for obtaining the compound as a free base. The optimum pH is between pH6 and 9, preferably between pH6 and 8.

The compound represented by formula (IV-c-Boc-059) can be isolated by diluting the reaction mixture with an organic solvent, adjusting the mixture to the optimum pH, and extracting the mixture with a solvent. The organic solvent used to dilute the alkaline reaction mixture is diethyl ether, ethyl acetate, butyl acetate, toluene, dichloromethane and chloroform, preferably ethyl acetate or dichloromethane.

In addition, the step of removing the tert-butoxycarbonyl group of the compound represented by the above formula (IV-b3-Cbz-059) by treatment with acid to obtain the compound of the above formula (IV-c-Cbz-059) is carried out as follows.

The solvent used to remove the t-butoxycarbonyl group may be water, methanol, ethanol, isopropanol, ethyl acetate, dioxane, dichloromethane, chloroform, 1,2-dichloroethane and 2,2,2-trifluoroethanol, preferably methanol, ethanol, ethyl acetate, dioxane and dichloromethane, which can be used alone or in combination.

The acid used in the reaction is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, chloromethanesulfonic acid and tetrafluoroboric acid, preferably hydrochloric acid, sulfuric acid, methanesulfonic acid and trifluoroacetic acid, more preferably hydrochloric acid or trifluoroacetic acid. The acid is used in the amount of 1 equivalent of the solvent with respect to the compound represented by the formula (IV-b3-Cbz-059), preferably 5 times the solvent.

The reaction temperature is -25 to 50°C, preferably -10 to 30°C. The reaction time is 1 to 6 hours, preferably 1 to 3 hours.

The compound represented by the formula (IV-c-Cbz-059) having the RcONHCO group, which exhibits the properties of a weak acid, is an amphoteric substance so as to obtain an optimal pH range for obtaining the compound as a free base. The optimum pH is between pH6 and 9, preferably between pH6 and 8.

The compound represented by formula (IV-c-Cbz-059) can be isolated by diluting the reaction mixture with an organic solvent, adjusting the mixture to the optimum pH, and extracting the mixture with a solvent. The organic solvent used to dilute the alkaline reaction mixture is diethyl ether, ethyl acetate, butyl acetate, toluene, dichloromethane and chloroform, preferably ethyl acetate or dichloromethane.

The step of removing 2-trimethylsilylethoxycarbonyl from the compound represented by the formula (IV-b4-Boc-059) with fluoride to obtain the compound represented by the above formula (IV-c-Boc-059) can be carried out as follows.

The solvent used to remove 2-trimethylsilylethoxycarbonyl may be water, methanol, ethanol, isopropanol, ethyl acetate, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide and dimethylacetamide, preferably dioxane, tetrahydrofuran and acetonitrile.

The fluoride used for the reaction is sodium fluoride, potassium fluoride, cesium fluoride, hydrofluoric acid, hydrogen fluoride - pyridine, tetrabutylammonium fluoride, preferably tetrabutylammonium fluoride, and is used in an amount of 2 to 6 equivalents with respect to the compound represented by the formula (IV-b4-Boc-059), preferably 2 to 3 equivalents.

The reaction temperature is 0 to 100°C, preferably 25 to 60°C. The reaction is carried out for 1 to 48 hours, preferably 12 to 24 hours.

The compound represented by formula (IV-c-Boc-059) can be isolated by diluting the reaction mixture with an organic solvent, adjusting the mixture to the optimum pH, and extracting the mixture with the solvent as described for formula (IV-b2-Boc-059). The organic solvent used to dilute the alkaline reaction mixture is diethyl ether, ethyl acetate, butyl acetate, toluene, dichloromethane and chloroform, preferably ethyl acetate.

Then, the step of obtaining a compound represented by the following formula (IIa-Boc-059) or (IIa-Cbz-059):

in the above formulas (IIa-Boc-059) or (IIa-Cbz-059), Boc is t-butoxycarbonyl, Cbz is benzyloxycarbonyl and OBn is benzyloxy,

silylation of the compound represented by the above formula (IV-c-Boc-059) or (IV-c-Cbz-059) in the reaction system while continuously carrying out the intramolecular urea formation reaction is carried out as follows.

The solvent used in the reaction is ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dichloromethane, chloroform, 1,2-dichloroethane, etc., preferably acetonitrile.

The organic base used in this reaction is triethylamine, diisopropylethylamine, tributylamine, N-methylmorpholine, etc., preferably triethylamine, and is used in an amount of 3 to 6 equivalents with respect to the compound represented by formula (IV-c-Boc-059) or formula (IV-c-Cbz-059), preferably 3 to 4 equivalents.

The silylating agent used in the reaction is chlorotrialkylsilane such as chlorotrimethylsilane, chlorotriethylsilane, chlorotriisopropylsilane and chloro-t-butyldimethylsilane; trimethylsilyl trifluoromethanesulfonate and t-butyldimethylsilyl trifluoromethanesulfonate, preferably chlorotrimethylsilane, and it is used in an amount of 1 to 3 equivalents with respect to the compound represented by formula (IV-c-Boc-059) or formula (IV-c-Cbz-059), preferably 1 to 2 equivalents.

The urea forming agent used in the reaction is phosgene, diphosgene, triphosgene and carbonyldiimidazole, preferably phosgene and diphosgene, and is used in an amount of 0.5 to 2 equivalents with respect to the compound represented by formula (IV-c-Boc-059) or formula (IV-c-Cbz-059), preferably 0.5 to 1.0 equivalents. At this time, to complete the formation of urea, the catalytic amount of 4-dimethylaminopyridine is used in an amount of 0.1 to 1 equivalent with respect to the compound represented by formula (IV-c), preferably 0.1 to 0.2 equivalent. The reaction temperature is -25 to 50°C, preferably -15 to 30°C. The reaction is carried out for 10 minutes to 24 hours, preferably 10 minutes to 16 hours.

The resulting compound represented by formula (IIa-Boc-059) or (IIa-Cbz-059) can be isolated by conventional post-treatment such as evaporating the organic solvent from the reaction mixture to concentrate it, diluting it with a solvent, washing with acid and base, drying, and evaporating the solvent to concentrate the mixture.

Then, the step of obtaining a compound represented by the following formula (IIb-Boc-059):

in the above formula (IIb-Boc-059), Boc is t-butoxycarbonyl,

cleaving benzyl from benzyloxy at the 6-position of a compound represented by formula (IIa-Boc-059) using a hydrogenolysis catalyst under hydrogen atmosphere, or

removal of benzyl from the benzyloxy at the 6-position of the compound represented by formula (IIa-Cbz-059) using a hydrogenolysis catalyst under a hydrogen atmosphere, while tert-butoxycarbonylation is carried out as follows.

The solvent used in this reaction is water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran and dioxane, preferably methanol or tetrahydrofuran, which can be used alone or in combination.

The hydrogenolysis catalyst is platinum oxide, palladium hydroxide, palladium black or palladium on charcoal, preferably palladium on charcoal.

The catalyst is used in an amount of 5 to 50% by mass in dry weight relative to the compound represented by formula (V-2), preferably 5 to 20% by mass.

The hydrogen source used for hydrogenolysis is hydrogen gas, and the hydrogen pressure is selected in the range of atmospheric pressure to 1 MPa, more preferably atmospheric pressure to 0.5 MPa. Alternatively, ammonium formate, cyclohexene, or cyclohexadiene can be used as the hydrogen source. The amount of hydrogen supplied is at least a stoichiometric amount.

The hydrogenolysis reaction temperature is 10 to 50°C, preferably 15 to 30°C. The reaction is carried out for 0.5 to 3 hours, preferably 0.5 to 2 hours. As for the compound represented by formula (IIa-Cbz-059), if the compound has a benzyloxycarbonyl separable from the benzyloxy at the 6-position, it can be protected again with t-butoxycarbonyl in the presence of di-t-butoxycarbonyl dicarbonate simultaneously with the above hydrogenolysis reaction.

The amount of di-tert-butoxycarbonyl dicarbonate added is 1 to 2 equivalents with respect to the compound represented by formula (IIa-Cbz-059), preferably 1 to 1.2 equivalents. After completion of the reaction, the compound represented by the formula (IIb-Boc-059) obtained in the reaction system can be isolated by conventional operations such as filtering the catalyst and evaporating the solvent to concentrate the mixture.

Then, the step of obtaining a compound represented by the following formula (III-Boc-059):

in the above formula (III-Boc-059), Boc is t-butoxycarbonyl and M is H, pyridinium, sodium or tetrabutylammonium,

sulfation of the hydroxyl group at the 6-position of the compound represented by the formula (IIb-Boc-059) in the presence of an organic base can be carried out as follows.

The solvent used for sulfonation is water, methanol, ethanol, isopropanol, dichloromethane, chloroform, 1,2-dichloroethane, pyridine, acetonitrile, dimethylformamide, etc., preferably dichloromethane, pyridine or acetonitrile.

The organic base used in this reaction is triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 2-picoline, 3-picoline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopiperidine and N-methylimidazole, preferably pyridine, 2-picoline and 2,6-lutidine, and is used in the amount 1.0 to the amount of solvent, with respect to the compound represented by the formula (IIb-Boc-059), preferably in the amount of 3.0 to the amount of solvent.

The material used as the sulfating agent is chlorosulfonic acid, sulfur trioxide-pyridine complex, sulfur trioxide-dimethylformamide complex, sulfur trioxide-trimethylamine complex, and sulfur trioxide-triethylamine complex, preferably sulfur trioxide-pyridine complex, and is used in an amount of 1 to 4 equivalents based on the compound represented by formula (IIb-Boc-059), preferably 1 to 3 equivalents .

The reaction temperature is 0 to 50°C, preferably 10 to 30°C. The reaction is carried out for 12 to 48 hours, preferably 12 to 24 hours.

After completion of the reaction, the compound represented by the formula (III-Boc-059) can be obtained as a pyridinium salt of sulfonic acid by filtration and evaporation of the solvent to concentrate the reaction mixture, and treatment with an aqueous solution of an inorganic base containing sodium, such as an aqueous solution of sodium bicarbonate, to obtain a sodium salt, removing excess organic base by washing with a solvent, and adding 1 to 3 molar equivalents, preferably 1 to 2 equivalents of tetrabutylammonium hydrogen sulfate, and extraction with an organic solvent such as ethyl acetate to give a tetrabutylammonium salt which can be used in the next step without purification.

Further, the step of obtaining the above (III-059) by deprotecting the t-butoxycarbonyl compound represented by the formula (III-Boc-059) with an acid selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid and tetrafluoroboric acid is carried out as follows.

The solvent used in the reaction is water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, 2,2,2-trifluoroethanol, etc., preferably dichloromethane or 2,2,2-trifluoroethanol.

The acid used in acidic deprotection is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, chloromethanesulfonic acid, tetrafluoroboric acid, etc., preferably hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and tetrafluoroboric acid. The acid is used in an amount of 1 equivalent to the amount of the solvent with respect to the compound represented by the formula (III-Boc-059), preferably 5 times the amount of the solvent. The reaction is carried out at -25 to 50°C, preferably -10 to 30°C. The reaction is carried out for 30 minutes to 5 hours, preferably 30 minutes to 1 hour.

After deprotection is completed, the solvent from the reaction mixture is evaporated to concentrate the mixture, the resulting residue is converted into an aqueous solution with optimal pH and subjected to purification with octadecyl-silica (ODS), synthetic polymer such as HP-20 and SP207, or ion exchange resin such as Dowex 50W-X8 (Na type), the solvent is evaporated to concentrate the mixture and re-precipitation or lyophilization to obtain the compound shown formula (III-059).

Here, the optimum pH means the pH at which the compound represented by the formula (III-059) is able to exist stably as an intramolecular salt. The pH range of 4 to 7 is chosen to isolate the compound as an intramolecular salt, more preferably pH 5 to 6.

EXAMPLES

Hereinafter, the present invention is illustrated in more detail by means of examples, but the present invention is not limited to these examples, and various modifications are possible.

Reference Example 1

(2S,5S)-1-Benzyl 2-tert-butyl 5-hydroxypiperidine-1,2-dicarboxylate (1)

Stage 1: (S)-1-Benzyl-2-tert-butyl 5-oxopyrrolidine-1,2-dicarboxylate

(S)-1-(Benzyloxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid (100 g) was dissolved in anhydrous methylene chloride (2 L), and concentrated sulfuric acid (10 ml) and isobutene (213 g) were added under ice-cooling, then the mixture was stirred overnight at +20°C or less. The reaction mixture was added to a cold aqueous sodium carbonate solution, paying attention to foaming, then the organic phase was separated, washed with saturated brine and dried over anhydrous magnesium sulfate, then the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=7/3) and crystallized from hexane/ethyl acetate to obtain 80 g of the title compound as a colorless crystalline powder (yield: 67%). 99.9% ee or more enantiomeric excess (CHIRALPAK AD-H, 4.6 x 150 mm, UV 210 nm, hexane/ethanol=2/1, flow rate 1 ml/min, retention time 4.2 min).

[α] ²⁰ _D -43.3° (c 0.52 in CHCl ₃ ), according to non-patent document [Journal of Medicinal Chemistry 1991, 34(3), 956-968. Dolence, E.K.; Lin, C.E.; Miller, MJ.; Payne, S.M. "Synthesis and siderophore activity of albomycin-like peptides derived from N5-acetyl-N5-hydroxy-L-ornithine"] -41.8° (c 6.71, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.39 (s, 9H), 2.04 (m, 1H), 2.32 (m, 1H), 2.51 (ddd, J=17.6, 9.5, 3.2 Hz, 1H), 2.62 (ddd, J=17.6, 10.5, 9.5 Hz, 1H), 4.55 (dd, J=9.5, 2.7 Hz, 1H), 5.25 (d, J=12.2 Hz, 1H), 5.30 (d, J=12.2 Hz, 1H), 7.26-7.41 (m, 5H); MS m/z 320 (M+H).

Stage 2: (S)-tert-Butyl 2-(benzyloxycarbonylamino)-5-oxo-6-dimethylsulfoxonium hexanoate

To a solution of trimethylsulfoxonium iodide (70.2 g) in anhydrous N,N-dimethylformamide (585 ml) under argon was added potassium tert-butoxide (36.8 g, 279 mmol), followed by stirring at room temperature for 1 hour. Then, at a temperature below 5°C or less, (S)-1-benzyl 2-tert-butyl 5-oxopyrrolidine-1,2-dicarboxylate (87.0 g) is added over 20 minutes (washed with anhydrous N,N-dimethylformamide (87 ml)), then left to react at the same temperature for 1 hour. The reaction mixture was added to ice water (2.6 L), saturated with sodium chloride, extracted with ethyl acetate (2.6 L x 1, 1.3 L x 2, 650 ml x 4), and the organic layer solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate=1/2→ethyl acetate/methanol=19/1→9/1) to obtain 112.3 g of the title compound as a pale yellow oil (quantitative).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.46 (s, 9H), 1.95 (m, 1H), 2.09 (m, 1H), 2.23-2.32 (m, 2H), 3.32 (s, 3H), 3.33 (s, 3H), 4.22 (m, 1H), 4.37 (s, 1H), 5.07 (d, J=12.0 Hz, 1H), 5.13 (d, J=12.0 Hz, 1H), 5.75 (brd, J=8.0 Hz, 1H), 7.30-7.36 (m, 5H); MS m/z 412 (M+H).

Stage 3: (S)-1-Benzyl 2-tert-butyl 5-oxo-piperidine-1,2-dicarboxylate

2-(Benzyloxycarbonylamino)-5-oxo-6-dimethylaminosulfoxonium (S)-tert-butyl hexanoate (24.8 g) was dissolved in 1,2-dichloroethane (774 ml) and after degassing, di-μ-chlorobis[(η-cycloocta-1,5-diene)diiridium (388.5 mg) was added under argon, then the temperature was raised and left interact at +70°C for 2 hours. The solvent of the reaction mixture was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 14.55 g of the red oil title compound (76% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,38 (с, 4,5H), 1,47 (с, 4,5H), 2,12-2,48 (м, 4H), 3,93 (д, J=19,0 Гц, 0,5H), 4,00 (д, J=18,8 Гц, 0,5H), 4,37 (д, J=18,8 Гц, 0,5H), 4,46 (д, J=19,0 Гц, 0,5H), 4,62 (дд, J=7,3, 6,6 Гц, 0,5H), 4,77 (дд, J=6,6, 5,9 Гц, 0,5H), 5,10-5,23 (м, 2H), 7,34-7,35 (м, 5H); MS m/z 334 (M+H).

Stage 4: (2S,5S)-1-Benzyl 2-tert-butyl 5-hydroxy-piperidine-1,2-dicarboxylate (1)

A solution of (S)-1-benzyl 2-tert-butyl-5-oxopiperidine-1,2-dicarboxylate (14.55 g) in ethanol (437 ml) was ice-cooled and sodium borohydride (1.65 g) was added, then allowed to react under ice-cooling for 20 minutes. A saturated ammonium chloride aqueous solution was added dropwise to the reaction mixture until the evolution of gas bubbles ceased, and the resulting salt was dissolved by adding water. The organic solvent of the mixture was evaporated under reduced pressure, and the aqueous layer of the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→2/1) to give 13.35 g of the title compound as a colorless oil (91% yield). Enantiomeric excess 98.8% ee (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, hexane/ethanol=4/1, flow rate 1 ml/min, retention time 9.1 min).

[α] ²⁰ _D -29.7° (c 1.3, CHCl ₃ ), according to non-patent document [Tetrahedron Asymmetry 2006, 17(17), 2479-2486. Jung, J.C.; Avery, M.A. "Diastereoselective synthesis of (2S,5S)-and (2S,5R)-N-benzyloxycarbonyl-5-hydroxypipecolic acids from trans-4-hydroxy-L-proline"] -27.9° (c 2.0, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,42 (с, 4,5H), 1,46 (с, 4,5H), 1,66-1,75 (м, 2H), 1,96-2,00 (м, 2H), 2,24-2,30 (м, 1H), 2,74-2,80 (м, 0,5H), 2,84-2,90 (м, 0,5H), 3,64 (шир.с, 1H), 4,15-4,20 (м, 0,5H), 4,23-4,27 (м, 0,5H), 4,65 (д, J=5,4 Гц, 0,5H), 4,78 (д, J=4,6 Гц, 0,5H), 5,07 (д, J=12,5 Гц, 1H), 5,21 (д, J=12,5 Гц, 1H), 7,26-7,37 (м, 5H); MS m/z 334 (M+H).

Sequential synthesis of (2S,5S)-1-benzyl 2-tert-butyl 5-hydroxy-piperidine-1,2-dicarboxylate (1)

2-(Benzyloxycarbonylamino)-5-oxo-6-dimethylsulfoxonium (S)-tert-butyl hexanoate (112.3 g, 272 mmol) is dissolved in 1,2-dichloroethane (3.4 L) and, after degassing, di-μ-chlorobis-[(η-cycloocta-1,5-diene)]diiridium (I) (1.83 g) is added in an argon atmosphere, then raise the temperature to +70°C for 1.75 hours and leave to interact for 1 hour. After cooling to room temperature, the solvent from the reaction mixture was evaporated under reduced pressure, and the resulting residue was dissolved in ethanol (1.1 L). The mixture is ice-cooled and sodium borohydride (5.14 g) is added over 10 minutes, then allowed to react under ice-cooling for 20 minutes. A saturated ammonium chloride aqueous solution (265 ml) was added dropwise to the reaction mixture until foaming was converted, and the resulting salt was dissolved by adding water (250 ml). The organic solvent was evaporated under reduced pressure and the aqueous layer of the residue was extracted with ethyl acetate (0.9 L×3 times). The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (heptane/ethyl acetate=3/1→2/1) to obtain 66.82 g of the title compound as a colorless oil (yield: 73%). The measurement results are consistent with those obtained in Step 4 of Reference Example 1.

Reference Example 2

Tetrahydro-2H-pyran-4-carbohydrazide

A solution of methyl tetrahydro-2H-pyran-4-carboxylate (1.44 g, 10.0 mmol) in methanol (50 ml) was stirred at 50°C. Hydrazine monohydrate (0.675 g) was added to the reaction mixture, followed by stirring at the same temperature for 2 hours, after completion of the reaction, the reaction mixture was concentrated and diluted with methylene chloride, then the solution was washed with saturated sodium bicarbonate aqueous solution and saturated brine, and the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 952 mg of the title compound (yield 66.1%).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.59-1.83 (m, 4H), 2.37-2.60 (m, 1H), 3.38-3.47 (m, 2H), 3.87-3.96 (m, 2H); MS m/z 145 [M+H] ⁺ .

Reference Example 3

Benzyl 2-(furan-2-carbonyl)hydrazinecarboxylate

Benzyl hydrazine carboxylate (1.66 g, 10.0 mmol) is dissolved in tetrahydrofuran (20 ml) and water (20 ml) and sodium hydrogen carbonate (1.68 g) is added. Under ice-cooling, furan-2-carbonyl chloride (1.30 g, 10 mmol) was gradually added, followed by stirring for 1 hour. After completion of the reaction, 300 ml of ethyl acetate was added to the reaction solution, followed by washing with a saturated ammonium chloride solution and a saturated saline solution. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and 5 ml of ethyl acetate was dissolved in the resulting residue, then hexane (100 ml) was gradually added to obtain 2.30 g of the title compound as a solid (yield: 88.4%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.18 (s, 2H), 6.51 (m, 1H), 6.91 (br s, 1H), 7.17 (m, 1H), 7.33 (m, 5H), 7.47 (m, 1H), 8.17 (br s, 1H); MS m/z 261 [M+H] ⁺ .

Reference Example 4

(R)-tert-Butyl 2-(2-((benzyloxy)carbonyl)hydrazinecarbonyl)-5-oxopyrrolidine-1-carboxylate

A solution of (R)-1-(tert-butoxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid (1.146 g, 5.00 mmol) in dry methylene chloride (25 ml) was cooled to 0°C under argon and isobutyl chloroformate (0.682 g) was gradually added dropwise so as not to exceed 0°C. Next, triethylamine (0.505 g) was gradually added so as not to exceed 0° C., followed by stirring for 30 minutes to obtain a mixed acid anhydride in the reaction system. To this reaction mixture was gradually added benzyl hydrazine carboxylate (0.830 g), after the addition, the temperature was raised to room temperature and stirred for 1 hour. This reaction mixture was washed with 0.5 M hydrochloric acid and brine, the organic layer was dried over magnesium sulfate and then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=30/1) to obtain 1.53 g of the title compound (80.1% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.45 (s, 9H), 2.20 (m, 2H), 2.45 (m, 1H), 2.63 (m, 1H), 4.59 (br s, 1H), 5.16 (m, 2H), 6.84 (br s, 1H), 7.33 (m, 5H), 8 .17 (broad s, 1H); MS m/z 378 [M+H] ⁺ .

Reference Example 5

(S)-tert-Butyl 2-(2-((benzyloxy)carbonyl)hydrazinecarbonyl)pyrrolidine-1-carboxylate

(S)-1-(tert-butoxycarbonyl)-pyrrolidine-2-carboxylic acid (1.076 g, 5.00 mmol) was stirred under argon at room temperature with dry methylene chloride (16 ml). N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 1.15 g), 1-hydroxybenzotriazole monohydrate (HOBt•H ₂ O, 0.918 g) and triethylamine (1.01 g) were then added, followed by stirring for 10 minutes. Benzyl hydrazine carboxylate (1.66 g) was added, then stirred for 18 hours. After completion of the reaction, the reaction solution was washed with 0.5 M hydrochloric acid and brine, then the organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, after which the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=30/1) to obtain 1.48 g of the title compound (yield 81.6%).

¹ H NMR (400 MHz, CDCl ₃ ): δ: 1.45 (s, 9H), 1.64 (m, 1H), 1.87-2.16 (m, 2H), 2.38 (m, 1H), 3.31-3.45 (m, 2H), 4.32 (m, 1H), 5.14-5.19 (m, 2H), 6 .68 (br.s, 1H), 7.34-7.40 (m, 5H), 8.76 (br.s, 1H); MS m/z 364 [M+H] ⁺ .

Reference Example 6

(S)-tert-Butyl 2-(2-((benzyloxy)carbonyl)hydrazinecarbonyl)-5-oxopyrrolidine-1-carboxylate

(S)-tert-Butyl 2-(2-((benzyloxy)carbonyl)hydrazinecarbonyl)pyrrolidine-1-carboxylate (1.089 g, 3.00 mmol) described in Reference Example 5 was dissolved in methanol (15 ml), 10% palladium-carbon (50% water content, 200 mg) was added, then stirred at room temperature for 1 hour under hydrogen atmosphere. The catalyst from the reaction mixture was filtered through Celite, and the solvent was concentrated under reduced pressure to give 595.5 mg of the title compound (86.6% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.41-1.45 (m, 9H), 1.80-1.99 (m, 3H), 2.15-2.22 (m, 1H), 2.26-3.50 (m, 2H), 4.08-4.15 (m, 1H); MS m/z 230 [M+H] ⁺ .

Reference Example 7

tert-Butyl (2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate

tert-Butyl (2-hydroxyethyl)carbamate (1.61 g, 10.0 mmol) was stirred under argon at room temperature with anhydrous tetrahydrofuran (50 ml). Next add triphenylphosphine (2.75 g) and N-hydroxyphthalimide (Pht-OH, 1.71 g). After ice-cooling the reaction mixture, diethyl azodicarboxylate (DEAD, 1.82 g) was gradually added dropwise, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the residue obtained after distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→1/1) to obtain 2.61 g of the title compound (yield 85.2%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.45 (s, 9H), 3.40-3.44 (m, 2H), 4.22-4.24 (m, 2H), 5.62 (br s, 1H), 7.73-7.85 (m, 4H); MS m/z 307 [M+H] ⁺ .

Reference Example 8

tert-Butyl (2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate

tert-Butyl (2-bromoethyl)carbamate (5.00 g, 23.5 mmol) was stirred under argon at room temperature with acetonitrile (74 ml). Then N-hydroxyphthalimide (Pht-OH, 3.83 g) and triethylamine (5.64 g) were added, then the reaction mixture was stirred at 70° C. for 24 hours. After completion of the reaction, the reaction solution was concentrated, diluted with ethyl acetate, and washed with 0.5M hydrochloric acid and saturated sodium bicarbonate aqueous solution, and the organic layer was dried over magnesium sulfate, ethyl acetate (10 ml) was added to the residue obtained after evaporating the solvent under reduced pressure, then hexane was added to obtain 4.72 g of the title compound (yield: 65.7%). The measurement results are comparable to the measurement results for the compound of Reference Example 7.

Reference Example 9

tert-Butyl 2-(aminooxy)ethylcarbamate

To a solution of tert-butyl (2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate (1.83 g, 6.00 mmol) described in Reference Example 7 in methylene chloride (11 ml) was gradually added a 9.8 M solution of methylamine in methanol (1.83 ml), followed by stirring for 2 hours. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure, then extracted with 0.5M hydrochloric acid (24 ml). Methylene chloride and 1M sodium hydroxide (18 ml) were added to the resulting aqueous layer, extracting the desired product with methylene chloride. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. 1.038 g of the title compound is obtained as a crude product (98% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.45 (m, 9H), 3.35-3.36 (m, 2H), 3.70-3.72 (m, 2H), 4.91 (br s, 1H), 5.47 (br s, 2H); MS m/z 177 [M+H] ⁺ .

Reference Example 10

Benzyl (2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate

Benzyl (2-hydroxyethyl)carbamate (5.857 g, 30.0 mmol) was stirred under argon at room temperature with dry tetrahydrofuran (150 ml). Next add triphenylphosphine (7.90 g) and N-hydroxyphthalimide (Pht-OH, 4.89 g). After cooling with ice, a solution of 2.2M diethyl azodicarboxylate in toluene (13.7 ml) was gradually added dropwise to the reaction mixture, and the mixture was stirred overnight at room temperature. After completion of the reaction, the residue obtained after evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain 9.36 g of the title compound (92% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 3.50-3.54 (m, 2H), 4.26-4.34 (m, 2H), 5.14 (br s, 2H), 5.98 (br s, 1H), 7.18-7.40 (m, 5H), 7.75-8.06 (m, 4H); MS m/z 358 [M+H] ⁺ .

Reference Example 11

Benzyl 2-(aminooxy)ethylcarbamate

To a solution of benzyl (2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate (9.36 g, 27.50 mmol) described in Reference Example 10 in methylene chloride (51 ml) was gradually added a solution of 9.8 M methylamine in methanol (8.50 ml), followed by stirring for 2 hours. The reaction solution was distilled off under reduced pressure, methylene chloride (50 ml) and water (80 ml) were added, adjusted to pH 1 with 5M hydrochloric acid, the aqueous layer was separated, and then washed with methylene chloride (50 ml). Methylene chloride (50 ml) was added to the resulting aqueous layer, adjusted to pH11 with 5M sodium hydroxide, the organic layer was separated, and then the aqueous layer was extracted twice with methylene chloride (50 ml). The combined organic layers were washed with an aqueous 50% potassium carbonate solution, then dried over anhydrous potassium carbonate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give 5.61 g of the title compound (97% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 3.42-3.46 (m, 2H), 3.72-3.74 (m, 2H), 5.10 (s, 2H), 5.15 (br s, 1H), 7.29-7.39 (m, 5H); MS m/z 211 [M+H] ⁺ .

Reference Example 12

2-(2-((Triisopropylsilyl)oxy)ethoxy)isoindoline-1,3-dione

Stage 1

2-(2-Hydroxyethoxy)isoindoline-1,3-dione

To a solution of N-hydroxyphthalimide (2.20 g, 13.5 mmol) and sodium acetate (3.30 g) in dimethyl sulfoxide (40 ml) was added 2-bromoethanol (2.88 ml) under argon at room temperature. The reaction mixture was stirred at 70°C for 5 hours, then cooled to room temperature, water (40 ml) was added and extracted with methylene chloride. The resulting organic layer was washed with water, 2.5M hydrochloric acid and brine. The washed organic layer was dried over magnesium sulfate, and the residue obtained after evaporating the solvent under reduced pressure was recrystallized from ethanol and water to obtain 1.86 g of the title compound (66% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ 3.84 (t, J=4.6 Hz, 2H), 4.26 (t, J=4.6 Hz, 2H), 7.89-7.80 (m, 4H); MS m/z 208 [M+H] ⁺ .

Stage 2

2-(2-((Triisopropylsilyl)oxy)ethoxy)isoindoline-1,3-dione

To a solution of 2-(2-hydroxyethoxy)isoindoline-1,3-dione (622 mg, 3.00 mmol) in dehydrated methylene chloride (6 ml) was added imidazole (306 mg) and chlorotriisopropylsilane (TIPSCl, 963 μl) under argon at room temperature. After the mixture was stirred at room temperature overnight, 2M hydrochloric acid was added to stop the reaction, then the methylene chloride was distilled off under reduced pressure. The obtained aqueous layer was extracted with ethyl acetate, then the aqueous layer was washed with saturated brine, and then dried over magnesium sulfate. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1→2/1) to obtain 1.04 g of the title compound (95% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.93-1.06 (m, 21H), 4.09 (t, J=4.8 Hz, 2H), 4.33 (t, J=4.8 Hz, 2H), 7.70-7.76 (m, 2H), 7.80-7.86 (m, 2H); MS m/z 364 [M+H] ⁺ .

Reference Example 13

(R)-tert-Butyl 3-(aminooxy)pyrrolidine-1-carboxylate

To (R)-tert-butyl 3-((1,3-dioxoisoindolin-2-yl)oxy)pyrrolidine-1-carboxylate (2.73 g, 8.21 mmol) obtained in a similar manner to Reference Example 7 from (R)-tert-butyl-3-hydroxypyrrolidine-1-carboxylate in methanol (43 ml), hydrazine monohydrate (1.54 g) was gradually added, then stirred within 2 hours. The reaction solution was filtered, and the residue obtained after distilling off the filtrate under reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→0/1) to obtain 1.30 g of the title compound (78.3% yield).

¹ H NMR (400 MHz CDCl ₃ ): δ 1.45 (m, 9H), 1.86-1.88 (m, 1H), 2.01-2.06 (m, 1H), 3.26-3.60 (m, 4H), 4.42 (br s, 1H); MS m/z 203 [M+H] ⁺ .

Reference Example 14

tert-Butyl 4-(2-((1,3-dioxoisoindolin-2-yl)oxy)acetyl)-1,4-diazepine-1-carboxylate

tert-Butyl 1,4-diazepine-1-carboxylate (2.00 g, 10.0 mmol) was stirred under argon under ice-cooling with anhydrous tetrahydrofuran (50 ml). After triethylamine (1.01 g) was added, chloroacetyl chloride (1.01 g) was gradually added. After completion of the reaction, N-hydroxyphthalimide (1.95 g) and triethylamine (2.22 g) are added. The reaction mixture is stirred at 60°C for 22 hours. After completion of the reaction, the reaction solution was concentrated, then diluted with ethyl acetate, washed with 8% citric acid and saturated sodium bicarbonate aqueous solution, and the organic layer was dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography and (hexane/ethyl acetate=4/1→0/1) to obtain 3.74 g of the title compound (93.0% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.45 (m, 9H), 1.85-1.99 (m, 2H), 3.37-4.11 (m, 8H), 4.84 (br s, 2H), 7.71-7.84 (m, 4H); MS m/z 404 [M+H] ⁺ .

Comparative Example 15

tert-Butyl 4-(2-(aminooxy)acetyl)-1,4-diazepine-1-carboxylate

To tert-butyl 4-(2-((1,3-dioxoisoindolin-2-yl)oxy)acetyl)-1,4-diazepine-1-carboxylate (2.14 g, 5.30 mmol) described in Reference Example 14 in methanol (16 ml) was gradually added a 9.8M solution of methylamine in methanol (1.62 ml), followed by stirring for 2 hours. The residue obtained by distilling the reaction solution under reduced pressure was dissolved in ethyl acetate (50 ml), then extracted with 0.25 M hydrochloric acid (20 ml). Methylene chloride and 0.3M sodium hydroxide (40 ml) were added to the resulting aqueous layer, and the title compound was extracted with methylene chloride. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. 1.298 g of the title compound are obtained as a crude product (89.6% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.45 (m, 9H), 1.85-1.99 (m, 2H), 3.36-3.63 (m, 8H), 4.37 (m, 2H), 5.92 (br s, 2H); MS m/z 274 [M+H] ⁺ .

Reference Example 16

tert-Butyl 2-(aminooxy)ethyl(methyl)carbamate

The title compound was prepared from tert-butyl 2-hydroxyethyl(methyl)carbamate according to the method described in Reference Example 7 and Reference Example 13.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.46 (s, 9H), 2.88 (br s, 3H), 3.36-3.53 (m, 2H), 3.75 (t, J=6.2 Hz, 2H), 5.30-5.75 (m, 2H); MS m/z 191 [M+H] ⁺ .

Reference Example 17

tert-Butyl (2-(aminooxy)ethyl)(isopropyl)carbamate

The title compound was prepared from tert-butyl 2-hydroxyethyl(isopropyl)carbamate according to the method described in Reference Example 7 and Reference Example 15.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.15 (d, J=6.4 Hz, 6H), 1.47 (s, 9H), 3.22-3.44 (m, 2H), 3.72 (t, J=6.4 Hz, 2H), 3.82-4.45 (m, 1H), 5.30-5.71 (m, 2H); MS m/z 219 [M+H] ⁺ .

Comparative Example 18

2-(aminooxy)-N,N-dimethylethanamine dihydrochloride

The title compound was obtained from J. Med. Chem. , 2000, 43(15), pp. 2332-2349.

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.80 (s, 6H), 3.43 (t, J=4.6 Hz, 2H), 4.44 (d, J=4.6 Hz, 2H), 11.2 (br s, 2H); MS m/z 105 [M-2HCl+H] ⁺ .

Reference Example 19

(S)-tert-Butyl (1-(aminooxy)propan-2-yl)carbamate

The title compound was prepared from (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate according to the method described in Reference Example 7 and Reference Example 15.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.12 (d, J=6.8 Hz, 3H), 1.45 (s, 9H), 3.43-3.54 (m, 1H), 3.64 (dd, J=11.2, 4.0 Hz, 1H), 4.00 (br s, 1H), 4.64 (br s, 1H), 5.57 (br s, 1H), 6.64 (br s, 1H); MS m/z 191 [M+H] ⁺ .

Reference Example 20

tert-Butyl 3-(aminooxy)propyl carbamate

The title compound was prepared from t-butyl 3-hydroxypropyl carbamate according to the method described in Reference Example 7 and Reference Example 13.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.44 (s, 9H), 1.68-1.82 (m, 2H), 3.14-3.27 (m, 2H), 3.73 (t, J=6.0 Hz, 2H), 4.77 (br s, 1H), 5.40 (br s, 2H); MS m/z 191 [M+H] ⁺ .

Reference Example 21

(S)-tert-Butyl 2-((aminooxy)methyl)azetidine-1-carboxylate

The title compound was prepared from (S)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate according to the method described in Reference Example 7 and Reference Example 15.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.45 (s, 9H), 1.97-2.11 (m, 1H), 2.19-2.30 (m, 1H), 3.78-3.93 (m, 4H), 4.42 (br s, 1H), 5.62 (br s, 1H); MS m/z 203 [M+H] ⁺ .

Reference Example 22

(R)-tert-Butyl 2-(aminooxy)pyrrolidine-1-carboxylate

The title compound was prepared from (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate according to the method described in Reference Example 7 and Reference Example 13.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.47 (s, 9H), 1.68-1.97 (m, 4H) 3.33 (br s, 2H), 3.56 (br s, 1H), 3.61-3.82 (m, 1H), 3.88-4.26 (m, 1H), 5.37-5.74 ( m, 2H); MS m/z 217 [M+H] ⁺ .

Reference Example 23

(S)-tert-Butyl 2-((aminooxy)methyl)piperidine-1-carboxylate

The title compound was prepared from (S)-tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate according to the method described in Reference Example 7 and Reference Example 15.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.32-1.76 (m, 6H), 1.47 (s, 9H), 2.71-2.84 (m, 1H), 3.56 (dd, J=11.2, 5.2 Hz, 1H), 3.86-4.04 (m, 2H), 4.59 (br s, 1H ), 5.64 (br s, 2H); MS m/z 231 [M+H] ⁺ .

Reference Example 24

(S)-tert-Butyl 3-(aminooxy)pyrrolidine-1-carboxylate

(S)-tert-Butyl 3-((1,3-dioxoisoindolin-2-yl)oxy)pyrrolidine-1-carboxylate (2.91 g, 8.77 mmol) obtained from (R)-tert-butyl-3-hydroxypyrrolidine-1-carboxylate according to the method described in Reference Example 7 was gradually added to methanol (43 ml) and hydrazine monohydrate (1, 54 g), then stirred for 3 hours. The reaction solution was filtered, and the residue obtained by distilling the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1→0/1) to obtain 1.75 g of the title compound (98.7% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.42 (m, 9H), 1.86 (m, 1H), 2.01-2.06 (m, 1H), 3.28-3.60 (m, 4H), 4.23 (br s, 1H); MS m/z 203 [M+H] ⁺ .

Reference Example 25

tert-Butyl 3-((aminooxy)methyl)azetidine-1-carboxylate

The title compound was prepared from t-butyl 3-(hydroxymethyl)azetidine-1-carboxylate according to the method described in Reference Example 7 and Reference Example 15.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.43 (s, 9H), 2.68-2.90 (m, 1H), 3.57-3.88 (m, 4H), 3.88-4.09 (m, 2H), 5.43 (br s, 2H); MS m/z 203 [M+H] ⁺ .

Example 1

(2S,5S)-tert-Butyl 5-hydroxypiperidine-2-carboxylate (2)

To a solution of (2S,5S)-1-benzyl 2-tert-butyl 5-hydroxypiperidine-1,2-dicarboxylate (67.2 g) described in Reference Example 1 in ethanol (900 ml) was added 10% palladium-carbon (water content about 50%, 10.1 g) and the mixture was vigorously stirred under a hydrogen atmosphere at room temperature overnight. The catalyst from the mixture was filtered off through Celite and the filtrate was concentrated to give 39.3 g of the title compound as a colorless solid (97% yield). Enantiomeric excess of 99% ee or more (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, diethylamine/hexane/ethanol=0.1/80/20, flow rate 1 ml/min, retention time 6.3 min).

[α] ²⁰ _D -28.7° (c 1.01, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.47 (s, 9H), 1.63 (m, 1H), 1.79-1.84 (m, 3H), 2.82 (dd, J=12.2, 2.2 Hz, 1H), 3.02 (ddd, J=12.2, 3.7, 1.7 Hz, 1H), 3, 21 (m, 1H), 3.80 (m, 1H); MS m/z 202 [M+H] ⁺ .

Example 2

(2S,5S)-tert-Butyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (3)

A solution of (2S,5S)-tert-butyl 5-hydroxypiperidine-2-carboxylate (39.14 g, 194 mmol) in dry tetrahydrofuran (450 ml) was cooled to -3 to -5° C. under argon, then triethylamine (78.7 g) was added and trifluoroacetic anhydride (81.5 g) was added dropwise over 30 min. The reaction mixture is reacted at -3 to -5°C for 1 hour, then water (90 ml) is added, the temperature is raised to room temperature and stirred for 1 hour. Water (740 ml) was added to the reaction mixture, extracted with ethyl acetate (450 ml × three times), and the combined organic layers were washed successively with 5% aqueous citric acid solution (450 ml), 6.5% aqueous sodium bicarbonate solution (450 ml) and water (450 ml). The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 50.06 g of the title compound as a pale yellow solid (87% yield). Enantiomeric excess 99% ee or more (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, hexane/ethanol=4/1, flow rate 1 ml/min, retention time 4.2 min).

[α] ²⁰ _D -54.1° (c 0.73, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ получают в виде смеси 2 ротамеров (7:3) 1,26-1,43 (м, 1H), 1,46 (с, 2,7H), 1,47 (с, 6,3H), 1,68-1,77 (м, 1H), 1,81 (д, J=4,8 Гц, 0,3H), 1,89 (д, J=5,2 Гц, 0,7H), 2,05-2,08 (м, 1H), 2,36-2,42 (м, 1H), 2,77 (дд, J=12,2, 12,0 Гц, 0,3H), 3,12 (дд, J=13,2, 10,7 Гц, 0,7H), 3,68-3,77 (м, 1H), 4,00 (м, 1H), 4,52-4,60 (м, 0,6H), 5,07 (д, J=5,9 Гц, 0,7H); MS m/z 298 [M+H] ⁺ .

Example 3

(2S,5R)-tert-Butyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (IV)

A solution of (2S,5S)-tert-butyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (10.22 g, 34.38 mmol) in anhydrous acetonitrile (113 ml) was cooled to -30 to -40° C. under argon, then 2,6-lutidine (4.4 ml) was added, then dropwise trifluoromethanesulfonic acid anhydride (5.92 ml) was added over 10 minutes, and further reacted at -30° C. for 15 minutes. To this reaction mixture was added benzyloxyamine (8.46 g) (washed with acetonitrile (5 ml)), then the temperature was raised to 0°C over 30 minutes, then 2,6-lutidine (4.4 ml) was added and reacted at 0 to 5°C for 3.5 days. This reaction mixture was concentrated under reduced pressure, the resulting residue was diluted with ethyl acetate (200 ml), then washed successively with water (200 ml), 10% aqueous citric acid solution (200 ml x three times), 6.5% aqueous sodium bicarbonate solution (100 ml) and brine (100 ml). Each aqueous layer was re-extracted with ethyl acetate (100 ml), the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain 11.69 g of the title compound as a colorless oil (85% yield). Enantiomeric excess 99.0% ee (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, hexane/ethanol=9/1, flow rate 1 ml/min, retention time 4.5 min).

[α] ²⁰ _D -45.6° (c 0.73, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ получают в виде смеси 2 ротамеров (7:3) 1,46 (с, 2,7H), 1,48 (с, 6,3H), 1,62-1,65 (м, 2H), 1,93-2,05 (м, 2H), 3,13 (м, 0,3H), 3,24-3,29 (м, 1H), 3,46 (м, 0,7H), 4,12 (м, 0,3H), 4,58-4,77 (м, 2,7H), 5,06 (м, 0,7H), 5,38 (м, 1H), 7,30-7,36 (м, 5H); MS m/z 403 [M+H] ⁺ .

Example 4

(2S,5R)-tert-Butyl 5-(benzyloxyamino)piperidine-2-carboxylate (4а)

To a solution of (2S,5R)-tert-butyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (6.91 g, in 17.17 mmol) in 1,4-dioxane (34 ml) was added water (9.2 ml), then 2.5M sodium hydroxide (13.7 ml) was added dropwise under ice-cooling, and leave to interact at the same temperature for 0.5 hours. Acetic acid (about 1 ml) was added to the reaction mixture, then concentrated under reduced pressure, and the resulting concentrated residue was extracted with ethyl acetate (58 ml, 29 ml). Each organic layer was washed with 50% potassium carbonate aqueous solution, and the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=19/1) to obtain 4.74 g of the title compound as a colorless oil (90% yield). Enantiomeric excess 98.9% ee (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, diethylamine/hexane/ethanol=0.1/80/20, flow rate 1 ml/min, retention time 5.5 min).

[α] ²⁰ _D -2.8° (c 0.73, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,28 (м, 1H, 1,42-1,46 (м, 10H), 1,92 (м, 1H), 2,04 (ддд, J=12,9, 7,3, 4,0 Гц, 1H), 2,43 (дд, J=12,0, 9,8 Гц, 1H), 2,98 (м, 1H), 3,16 (дд, J=11,0, 3,2 Гц, 1H), 3,57 (ддд, J=12,0, 4,2, 2,0 Гц, 1H), 4,68 (с, 2H), 7,29-7,35 (м, 5H); МС m/z 307 [M+H] ⁺ .

Example 5

Sequential synthesis of (2S,5R)-tert-Butyl 5-(benzyloxyamino)piperidine-2-carboxylate (4a)

A solution of (2S,5S)-tert-Butyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (47.9 g, 161 mmol) in dry acetonitrile (318 ml) was cooled to -30 to -40° C. under argon, then 2,6-lutidine (20.5 ml) was added, then added dropwise trifluoromethanesulfonic acid anhydride (28.4 ml) for 40 minutes, and then reacted at -30°C for 15 minutes. To this reaction mixture was added benzyloxyamine (39.7 g) (washed with acetonitrile (11 ml)) over 8 minutes, then the temperature was raised to 0°C over 30 minutes, more 2,6-lutidine (20.5 ml) was added and reacted at 0 to 5°C for 2 days. The reaction mixture was concentrated under reduced pressure, the resulting residue was diluted with ethyl acetate (960 ml) and washed successively with water (960 ml), 10% citric acid solution (960 ml x three times), 6.5% aqueous sodium bicarbonate solution (480 ml) and brine (480 ml). Each aqueous layer is re-extracted with ethyl acetate (960 ml), the organic layers are combined and the solvent is evaporated under reduced pressure. The resulting residue was dissolved in a solution of 1,4-dioxane (320 ml) and water (86 ml), then 2.5 M sodium hydroxide (128 ml) was added dropwise under ice-cooling and allowed to react at the same temperature for 0.5 hours. Acetic acid (ca. 9.3 ml) was added to the reaction mixture, then concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate (580 ml, 290 ml). Each organic layer was washed with 50% potassium carbonate aqueous solution (580 ml), then the combined organic layers and the solvent were evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=100/1→19/1) to obtain 36.58 g of the title compound as a colorless oil (74% yield). The measurement data are comparable to those from example 4.

Example 6

(2S,5R)-tert-Butyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (5a)

To a solution of (2S,5R)-tert-butyl 5-(benzyloxy)aminopiperidine-2-carboxylate (4.14 g, 13.51 mmol) in dry acetonitrile (615 ml) was added triethylamine (4.9 ml) under argon at 0°C, then diphosgene (1.18 ml) was added dropwise for 5 minutes and stirred at the same temperature in within 10 minutes. To this solution was added 4-dimethylaminopyridine (182 mg), then the temperature was raised to room temperature and allowed to react for 3 hours. The reaction mixture was concentrated under reduced pressure to one tenth by volume, the resulting concentrated solution was diluted with ethyl acetate, then washed successively with water, an aqueous 5% citric acid solution, an aqueous 6.5% sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 3.09 g of the title compound (69% yield). The solid obtained is recrystallized from ethyl acetate-hexane and the precipitate formed is filtered off. The wet crystals are washed with hexane, then dried at room temperature under reduced pressure to give the title compound as a colorless crystalline powder. Enantiomeric excess 99.4% ee (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 ml/min, retention time 8.0 min).

Mr 83°C; [α] ²⁰ _D +5.9° (c 0.61, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.48 (s, 9H), 1.62 (m, 1H), 2.00-2.10 (m, 3H), 2.98 (d, J=11.7 Hz, 1H), 3.03 (m, 1H), 3.30 (m, 1H), 4.01 (m, 1H), 4.90 (d, J=11.5 Hz, 1H), 5.06 (d, J=11.5 Hz, 1H), 7.35-7.42 (m, 5H); MS m/z 333 [M+H] ⁺ .

In the X-ray powder diffraction diagram, the crystal of the title compound shows the characteristic peaks shown in Table 1. For measurement, RINT2100 from Rigaku Corporation is used as an X-ray powder diffraction equipment, in which measurement is carried out with CuKα1 as an X-ray source, a tube voltage of 40 kV, a tube current of 40 mA, a scan rate of 4°/min, and a scan interval of 2Θ=3 to 40°.

Table 1
Powder X-ray diffraction pattern of compound (5a) Peak position Lattice period 2Θ Relative intensity (d) (Cuka) Å I/IO 7.64 11.56 13 8.06 10.96 67 13.50 6.55 46 14.74 6.00 15 15.30 5.79 eleven 15.92 5.56 44 16.18 5.47 58 16.86 5.25 64 18.10 4.90 46 20.38 4.35 18 20.96 4.23 100 23.04 3.86 10

Example 7

(2S,5R)-tert-Butyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (5a): reaction with phosgene

To a solution of (2S,5R)-tert-butyl 5-(benzyloxyamino)piperidine-2-carboxylate (3.0 g, 9.791 mmol) in dry acetonitrile (150 ml) under argon at room temperature were added triethylamine (3.82 ml) and 4-dimethylaminopyridine (120 mg), and phosgene (obtained by adding diphosgene (1.548 g) dropwise to activated charcoal (1 g) heated to 60° C. for 1.5 hours) under argon flow, then stirred overnight. The excess phosgene is decomposed with concentrated aqueous ammonia (0.6 ml) and the solvent of the reaction mixture is concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 ml), washed successively with water (50 ml), 5% aqueous citric acid solution (50 ml), 6.5% aqueous sodium bicarbonate solution (25 ml) and brine, then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 2.25 g of the title compound (69% yield). The resulting solid is recrystallized from ethyl acetate-hexane, the resulting precipitate is filtered off. The wet crystal was washed with hexane and then dried under reduced pressure at room temperature to obtain the title compound as a colorless crystalline powder. The measurement data are comparable to those from example 6.

Example 8

Cyclohexylamine (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (6a)

To a solution of (2S,5R)-tert-Butyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (270 mg, 0.842 mmol) in methylene chloride (2 mL) was added trifluoroacetic acid (2 mL) under argon at 0°C and the temperature was raised to room temperature, then reacted for 4 hours. The reaction mixture was concentrated, and the resulting residue was diluted with ethyl acetate, washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in ethyl acetate (2.5 ml), and then a solution of cyclohexylamine (149 mg) in diethyl ether was added at room temperature, followed by stirring at 0° C. for 1 hour. The resulting precipitate was filtered off, and the filter cake was washed with diethyl ether, then dried at room temperature under reduced pressure to give 270 mg of the title compound as a colorless crystalline powder (86% yield).

Mr 175°C; [α] ²⁰ _D -36.8° (c 0.50, H ₂ O); ¹ H ЯМР (400 МГц, диметилсульфоксид): δ 1,00-1,30 (м, 5H), 1,53-1,95 (м, 8H), 2,04-2,09 (м, 1H), 2,76 (д, J=11,6 Гц, 1H), 2,80-2,93 (м, 1H), 3,19 (д, J=11,2 Гц, 1H), 3,33 (шир.с, 2H), 3,40 (д, J=7,2 Гц, 1H), 3,51 (шир.с, 1H), 4,87 (д, J=11,6 Гц, 1H), 4,93 (д, J=11,6 Гц, 1H), 7,30-7,45 (м, 5H), 8,04 (шир.с, 1H); MS m/z 100, 277 [MC ₆ H ₁₃ N+H] ⁺ .

In the X-ray powder diffraction diagram, the crystal of the title compound shows the characteristic peaks shown in Table 2. For measurement, RINT2100 from Rigaku Corporation is used as an X-ray powder diffraction equipment, in which measurement is carried out with CuKα1 as an X-ray source, a tube voltage of 40 kV, a tube current of 40 mA, a scan rate of 4°/min, and a scan interval of 2Θ=3 to 40°.

table 2
Powder X-ray diffraction pattern of compound (6a) Peak position Lattice period 2Θ Relative intensity(d) (Cuka) Å I/IO 8.88 9.95 46 10.46 8.45 9 14.14 6.26 14 15.08 5.87 17 16.04 5.52 100 16.98 5.22 71 17.38 5.10 17 17.88 4.96 26 18.74 4.73 57 19.52 4.54 22 21.36 4.16 13 22.60 3.93 68 25.08 3.55 12

Example 9

(2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (6b)

Cyclohexylamine (230 mg) of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in aqueous saturated sodium dihydrogen phosphate, then extracted 4 times with ethyl acetate, and the combined organic layers were washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and dried in vacuo to give 161 mg of the title compound as a colorless foamy solid (87% yield). Enantiomeric excess 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, trifluoroacetic acid/hexane/ethanol=0.1/80/20, UV 210 nm, flow rate 1 ml/min, retention time 15.5 min).

[α] _D ²⁰ +11.5° (c 0.56, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.67 (m, 1H), 2.04-2.26 (m, 3H), 2.85 (d, J=12.0 Hz, 1H), 3.13 (m, 1H), 3.35 (m, 1H), 4.12 (m, 1H), 4.91 (d, J=11.3 Hz, 1H), 5.06 (d, J=11.3 Hz, 1H), 7.37-7.44 (m, 5H); MS m/z 277 [M+H] ⁺ .

Example 10

(2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (6b); treatment with hydrochloric acid followed by crystallization

(2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid cyclohexylamine (3.75 g, 10.0 mmol) was dissolved in water (50 ml). Add ethyl acetate (100 ml) and 1M hydrochloric acid (20 ml). The mixture is stirred, then extracted three times with ethyl acetate (each time 100 ml). The organic layer was dried over anhydrous magnesium sulfate, the solvent was concentrated to 10 ml under reduced pressure. Gradually add 120 ml of hexane with stirring under ice-cooling and the resulting precipitate is filtered off. The resulting precipitate is filtered off. After washing the wet crystals with hexane, they were dried at room temperature under reduced pressure to obtain 2.44 g of the title compound as a colorless crystalline powder. So pl. 116°C; other measurement data are comparable to those from example 9.

In the X-ray powder diffraction diagram, the crystal of the title compound shows the characteristic peaks shown in Table 3. For measurement, RINT2100 from Rigaku Corporation is used as an X-ray powder diffraction equipment, in which measurement is carried out with CuKα1 as an X-ray source, a tube voltage of 40 kV, a tube current of 40 mA, a scan rate of 4°/min, and a scan interval of 2Θ=3 to 40°.

Table 3
Powder X-ray diffraction pattern of compound (6b) Peak position Lattice period 2Θ Relative intensity(d) (Cuka) Å I/IO 10.80 8.19 10 12.38 7.14 14 13.32 6.64 eleven 14.06 6.29 81 15.82 5.60 33 17.02 5.21 92 18.04 4.91 12 19.28 4.60 37 21.06 4.21 100 24.08 3.69 42 25.80 3.45 16 28.52 3.13 33

Example 11

(2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylic acid dihydrochloride (IV-a1)

To 5M hydrochloric acid (500 ml) was added (2S,5R)-tert-butyl 5-(benzyloxyamino)piperidine-2-carboxylate (46.69 g) and the mixture was stirred at 65°C for 2 hours. The reaction solution was cooled to room temperature, the residue obtained by concentrating the solvent under reduced pressure was dissolved in water (500 ml), then activated carbon (2.7 g) was added and stirred for 30 minutes. The activated charcoal was removed by filtration, the filtrate was concentrated to dryness and dried in vacuo overnight to give 49.3 g of the title compound, a pale yellow solid (quantitative).

¹ H ЯМР (400 МГц, D ₂ O): δ 1,39-1,49 (м, 1H), 1,59-1,70 (м, 1H), 1,88-1,95 (м, 1H), 2,20-2,28 (м, 1H), 2,78 (т, J=11,8 Гц, 1H), 3,19-3,28 (м, 1H), 3,48-3,52 (м, 1H), 3,68-3,72 (м, 1H), 3,57 (с, 3H), 3,70 (дд, J=3,4, 12,6 Гц), 4,68 (с, 2H), 7,26-7,32 (м, 5H); MS m/z 251 [M-2HCl+H] ⁺ .

Example 12

(2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate dihydrochloride (4b)

To 2M hydrochloride in methanol (7 ml) was added (2S,5R)-5-(benzyloxy)piperidine-2-carboxylic acid dihydrochloride (176 mg), then refluxed for 3 hours, the reaction mixture was concentrated under reduced pressure, dried in vacuo overnight to give the title compound as a pale yellow solid (quantitative yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.40-1.51 (m, 1H), 1.61-1.72 (m, 1H), 1.90-1.94 (m, 1H), 2.25-2.30 (m, 1H), 2.80 (t, J=11.2 Hz, 1H), 3.19-3.27 (m, 1 H), 3.51-3.55 (m, 1H), 3.66 (s, 3H), 3.87-3.91 (m, 1H), 4.68 (s, 2H), 7.27 (s, 5H); MS m/z 265 [M-2HCl+H] ⁺ .

Example 13

(2S,5R)-Methyl 5-(benzyloxyamino)piperidine-2-carboxylate (4b)

Ethyl acetate (20 ml) and 50% potassium carbonate aqueous solution (20 ml) were added to (2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate dihydrochloride (1.319 g) for liquid separation, and the aqueous layer was extracted three times with ethyl acetate (15 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered, then concentrated under reduced pressure and dried in vacuo overnight to give 975 mg of the title compound (94% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.25-1.35 (m, 1H), 1.49-1.59 (m, 1H), 1.89-2.11 (m, 2H), 2.45 (t, J=11.7 Hz, 1H), 2.96-3.03 (m, 1H), 3.28-3.92 (m, 2H), 3.72 (s, 3H), 4.68 (s, 2H), 7.26-7.35 (m, 5H); MS m/z 265 [M+H] ⁺ .

Example 14

Direct synthesis of (2S,5R)-methyl-5-(benzyloxyamino)piperidine-2-carboxylate dihydrochloride (4b)

The crude product (507 mg, 1.26 mmol of (2S,5R)-tert-butyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate described in Example 3 was dissolved in 2M hydrogen chloride in methanol (10.3 ml) and refluxed for 33 hours. The reaction mixture was concentrated under reduced pressure to a volume of approximately 3.6 ml, and ethyl acetate (10.3 ml) was added to the concentrated solution to precipitate.The resulting precipitate was collected by vacuum filtration, the filter cake was washed with a small amount of ethyl acetate, then dried through flow to give 290 mg of the title compound as a white powder (68% yield).

Example 15

(2S,5R)-methyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (5b)

To (2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate (1.154 g, 4.37 mmol) was added dry acetonitrile (198 ml), then cooled on ice. Triethylamine (1.60 ml) and diphosgene (0.389 ml) are added dropwise successively at 5°C or lower, and the mixture is stirred at 2°C for 20 minutes. Then, 4-dimethylaminopyridine (70.0 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, then displaced and concentrated with ethyl acetate three times and the solution was concentrated to 30 ml. Ethyl acetate (20 ml) and water (40 ml) were added, followed by liquid separation and the aqueous layer was extracted with ethyl acetate (30 ml) twice. The combined organic layers were washed with 5% aqueous citric acid (40 ml), 6.5% aqueous sodium bicarbonate (30 ml) and 5% brine (30 ml) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. 1.16 g of the resulting residue was diluted with ethyl acetate (5.5 ml) and n-hexane (11 ml) was added and the seed crystals were inoculated to crystallize. Then add n-hexane (49 ml) and stir at 0°C for 1 hour. The crystals are then filtered off, washed with n-hexane (60 ml), and then dried in vacuo to give 882.3 mg of the title compound as a colorless crystalline powder (71% yield).

Mr 86°C; [α] ²⁰ _D +5.3° (c 1.10, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.65-1.70 (m, 1H), 2.03-2.12 (m, 3H), 2.90 (d, J=12.0 Hz, 1H), 3.07 (m, 1H), 3.79 (s, 3H), 4.12 (dd, J=4.6, 4.4 Hz, 1H ), 4.91 (d, J=11.2 Hz, 1H), 5.06 (d, J=11.2 Hz, 1H), 7.35-7.44 (m, 5H); MS m/z 291 [M+H] ⁺ .

In the X-ray powder diffraction diagram, the crystal of the title compound shows the characteristic peaks shown in Table 4. For measurement, RINT2100 from Rigaku Corporation is used as the X-ray powder diffraction equipment, in which the measurement is carried out with CuKα1 as the X-ray source, the tube voltage is 40 kV, the tube current is 40 mA, the scan rate is 4°/min, and the scan interval 2Θ=3 to 40°.

Table 4
Powder X-ray diffraction pattern of compound (5b) Peak position Lattice period 2Θ Relative intensity(d) (Cuka) Å I/IO 8.50 10.39 92 15.10 5.86 9 15.56 5.69 66 16.60 5.34 eleven 18.42 4.81 28 19.98 4.44 100 22.30 3.98 9 23.50 3.78 66 28.64 3.11 13 29.44 3.03 19 30.52 2.93 13 32.28 2.77 eleven

Example 16

(2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (6b): Synthesis from (5b)

To (2S,5R)-methyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (809.0 mg, 2.79 mmol) was added tetrahydrofuran (8 ml) and water (3.6 ml), then 0.5M aqueous lithium hydroxide solution (6.41 ml) was added dropwise at 4.9°C over 10 minutes. The reaction solution was stirred at 2° C. for 2 hours, then water (30 ml) was added and washed with ethyl acetate (25 ml). Ethyl acetate (15 ml) was added to the separated aqueous layer, the aqueous layer was adjusted to pH 4.0 with 1M aqueous hydrochloric acid, and extracted twice with ethyl acetate (ethyl acetate: total volume 65 ml). The separated aqueous layer was adjusted to pH 3.4 with 1M aqueous hydrochloric acid and extracted once with ethyl acetate, then the aqueous layer was adjusted to pH 2.4 and extracted twice with ethyl acetate. The extraction liquid obtained after five extractions with ethyl acetate (175 ml) was washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 759.1 mg of the resulting residue was diluted with ethyl acetate (5 ml) and n-hexane (3 ml) was added and the seed crystals were inoculated to crystallize. Then add a solution of ethyl acetate/n-hexane (5/3) (8 ml) and stir, then add n-hexane (20 ml) and stir at 4°C for 14 hours. The crystals were filtered off, washed with n-hexane (55 ml), then dried in vacuo to give 633.6 mg of the title compound as a colorless crystalline powder (82% yield). The measurement data are comparable to those from example 9.

Example 17

(2S,5R)-7-Oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl 2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

To a solution of the carboxylic acid (6b, 371 mg, 1.34 mmol) from Example 9 or 16 in tetrahydrofuran (7 mL) was added triethylamine (0.227 mL) and isobutyl chloroformate (218 μL) under ice-cooling, then the mixture was stirred at 0°C for 15 min. To the reaction solution was added tert-butyl carbazate (245 mg) at 0° C., and the mixture was stirred at room temperature for 1.5 hours, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-0/1) to obtain 583 mg of the title compound (98% yield).

[α] _D ²⁰ +54.3° (c 0.56, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,47 (с, 9H), 1,56-1,67 (м, 1H), 1,90-2,05 (м, 2H), 2,34-2,41 (м, 1H), 3,04-3,17 (м, 2H), 3,26-3,31 (м, 1H), 4,00 (д, J=7,6 Гц, 1H), 4,91 (д, J=11,2 Гц, 1H), 5,06 (д, J=11,2 Гц, 1H), 6,31 (шир.с, 1H), 7,34-7,46 (м, 5H), 8,14 (д, J=2,8 Гц, 1H); MS m/z 391 [M+H] ⁺ .

Stage 2

tert-Butyl 2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

The compound (573 mg, 1.47 mmol) obtained in step 1 was dissolved in methanol (10 ml) and 10% palladium-carbon (water content 50%, 126 mg) was added, the mixture was stirred under hydrogen atmosphere at room temperature for 55 minutes. The catalyst from the reaction mixture was filtered through Celite, the solvent was concentrated under reduced pressure to give 423 mg of the title compound (96% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.48 (s, 9H), 1.70-1.82 (m, 1H), 1.86-1.98 (m, 1H), 2.01-2.12 (m, 1H), 2.27 (br.dd, J=14.6, 6.6 Hz, 1H), 3.11-3.25 ( m, 2H), 3.70 (br s, 1H), 3.91 (br d, J=7.2 Hz, 1H); MS m/z 301 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of compound (421 mg, 1.40 mmol) from step 2 in pyridine (10 ml) was added sulfur trioxide-pyridine complex (1.01 g) and the mixture was stirred at room temperature overnight. Methylene chloride was added to the reaction mixture after filtration, then concentrated under reduced pressure and adjusted to pH 8 by adding a half-saturated sodium bicarbonate aqueous solution. The aqueous layer was washed with methylene chloride. Then, tetrabutylammonium hydrogen sulfate (564 mg) and methylene chloride were added to the aqueous layer, followed by stirring for 15 minutes. The aqueous layer was extracted with methylene chloride, then the resulting organic layer was dried over anhydrous sodium sulfate, after filtration, and concentrated under reduced pressure to obtain 841 mg of tetrabutylammonium tert-butyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate tetrabutylammonium.

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,01 (т, J=7,4 Гц, 12H), 1,40-1,53 (м, 8H), 1,49 (с, 9H), 1,60-1,75 (м, 9H), 1,84-1,98 (м, 1H), 2,15-2,24 (м, 1H), 2,35-2,44 (м, 1H), 3,06-3,18 (м, 1H), 3,24-3,36 (м, 8H), 3,39 (шир.д, J=11,6 Гц, 1H), 3,97 (шир.д, J=7,2 Гц, 1H), 4,36 (шир.с, 1H), 6,31 (шир.с, 1H), 8,59-8,67 (м, 1H); MS m/z 381 [M-Bu ₄ N+2H] ⁺ .

All of the above tetrabutylammonium salt was dissolved in methylene chloride (15 ml), trifluoroacetic acid (5 ml) was added and stirred at room temperature for 1 hour. The reaction mixture is then concentrated under reduced pressure, and the resulting residue is washed with diethyl ether and dried. The resulting crude product was adjusted to pH 8 with aqueous sodium bicarbonate and purified by octadecyl silica gel column chromatography to give 227 mg of the title compound (2 steps, 58% yield).

[α] _D ²⁰ -52.9° (c 0.15, H ₂ O); ¹ H NMR (400 MHz, D ₂ O): δ 1.63-1.73 (m, 1H), 1.76-1.87 (m, 1H), 1.90-1.99 (m, 1H), 2.00-2.09 (m, 1H), 2.97 (d, J=12.2 Hz, 1H), 3.17 (brd, J=12, 2 Hz, 1H), 3.92 (d, J=7.2 Hz, 1H), 4.04-4.08 (m, 1H); MS m/z 281 [M+H] ⁺ .

Example 18

tert-Butyl 1-methyl-2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate sodium

Stage 1

tert-Butyl 2-{[(2SR,5RS)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate

To a solution of (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (400 mg, 1.45 mmol) and tert-butyl 1-methylhydrazinecarboxylate (232 mg) in tetrahydrofuran (14 ml) was added triethylamine (972 μl) and 2-chloro-1-methylpyri iodide din-1-ia (554 mg) and the mixture was stirred at room temperature overnight. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with chloroform. The organic layer is dried over sodium sulfate and then concentrated. The resulting crude product was purified by silica gel column chromatography to give 458 mg of the title compound (78% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.29-1.40 (m, 10H), 1.53-1.60 (m, 2H), 2.24-2.30 (m, 1H), 2.96-3.24 (m, 6H), 3.87 (d, J=1.7, 1H), 4.83 (d, J=2.8, 1H), 4.97 (d, J=2.8, 1H), 7.26-7.36 (m, 5H).

Stage 2

tert-Butyl 2-{[(2SR,5RS)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate

To a solution of the compound (485 mg, 1.20 mmol) from step 1 in methanol (14 ml) was added 50% palladium-carbon (water content 50%, 50 mg), the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst from the reaction mixture is filtered through a PTFE membrane, then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give 359 mg of the title compound (95% yield). MS m/z 315 [M+H] ⁺ .

Stage 3

tert-Butyl 1-methyl-2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate sodium

To a solution of the entire compound from step 2 in methylene chloride (10.0 ml) was added 2,6-lutidine (842 μl) and sulfur trioxide-pyridine complex (273 mg) and the mixture was stirred at room temperature overnight. Chloroform was added to the reaction solution, followed by liquid separation with water. The obtained pyridinium tert-butyl 2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate obtained in the aqueous layer was neutralized with saturated sodium bicarbonate aqueous solution and purified by octadecyl silica gel column chromatography with yielding 114 mg of the title compound (23% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.47 (s, 9H), 1.84 (m, 1H), 1.96-2.04 (m, 1H), 2.11-2.15 (m, 1H), 2.23-2.28 (m, 1H), 3.11 (s, 3H), 3.18 (d, J=3.0, 1 H), 3.41 (d, J=2.7, 1H), 4.15 (d, J=1.9, 1H), 4.25 (br s, 1H); MS m/z 393 [M-Na] ^- .

Example 19

(2SR,5RS)-N'-Methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

sodium tert-Butyl 1-methyl-2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate (100 mg, 0.24 mmol) from Example 18 was deprotected with trifluoroacetic acid and purified by octadecyl column chromatography silica gel to give 41 mg of the title compound (58% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.63-1.71 (m, 1H), 1.74-1.84 (m, 1H), 1.90-1.96 (m, 1H), 2.00-2.06 (m, 1H), 3.40 (s, 3H), 2.95 (d, J=3.0, 1H), 3.15 (d, J=3.0, 1H), 3.89 (d, J=1.6, 1H), 4.04 (br s, 1H), MS m/z 293 [MH] ^-

Example 20

(2SR,5RS)-N',N'-dimethyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-sodium carbohydrazide

Stage 1

(2SR,5RS)-6-Benzyloxy-N',N'-dimethyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Using a procedure analogous to Example 18, from (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (200 mg, 0.72 mmol) and 1,1-dimethylhydrazine (48 mg) 150 mg of the title compound was obtained (65% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.53 (m, 1H), 1.75-1.88 (m, 2H), 2.21-2.27 (m, 1H), 2.46 (s, 6H), 2.61 (d, J=2.6, 1H), 2.89 (d, J=2.6, 1H), 3.19-3, 21 (m, 1H), 3.75 (d, J=1.9, 1H), 4.78 (d, J=2.9, 1H), 4.92 (d, J=2.9, 1H), 7.16-7.31 (m, 5H).

Stage 2

(2SR,5RS)-N',N'-dimethyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

In a manner analogous to Example 18, 101 mg of the title compound was obtained from the total amount of the compound from Step 1 (94% yield). MS m/z 229 [M+H] ⁺ .

Stage 3

(2SR,5RS)-N',N'-dimethyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-sodium carbohydrazide

In a manner analogous to Example 18, pyridinium (2SR,5RS)-N',N'-dimethyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide, prepared from the total compound of Step 2, was neutralized with saturated aqueous sodium bicarbonate and purified by octadecyl silica gel column chromatography to give 65 mg of the title compound (44% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.80-1.98 (m, 2H), 2.07-2.20 (m, 2H), 2.59 (s, 6H), 3.11 (d, J=3.0, 1H), 3.33 (d, J=3.0, 1H), 4.01 (d, J=1.3, 1H), 4, 22 (broad s, 1H); MS m/z 307 [M-Na] ^- .

Example 21

(2S,5R)-N'-acetyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

(2S,5R)-N'-acetyl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of the carboxylic acid (6b, 2.37 g, 8.57 mmol) of Example 9 or 16 in tetrahydrofuran (50 ml) was added triethylamine (1.39 ml) and isobutyl chloroformate (1.32 ml) under ice-cooling, followed by stirring at 0°C for 20 minutes. Acetohydrazide (807 mg) was added to the reaction solution at 0° C., stirred at room temperature for 40 minutes, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 2.61 g of the title compound (92% yield).

[α] _D ²⁰ +92.3° (c 0.65, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,57-1,70 (м, 1H), 1,90-2,15 (м, 2H), 2,06 (с, 3H), 2,30-2,39 (м, 1H), 3,08 (шир.д, J=12,0 Гц, 1H), 3,13 (д, J=12,0 Гц, 1H), 3,31-3,37 (м, 1H), 4,02 (д, J=7,6 Гц, 1H), 4,92 (д, J=11,4 Гц, 1H), 5,06 (д, J=11,4 Гц, 1H), 7,33-7,50 (м, 5H), 7,72 (шир.с, 1H), 8,55 (шир.с, 1H); MS m/z 333 [M+H] ⁺ .

Stage 2

(2S,5R)-N'-acetyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

The compound (2.48 g, 7.46 mmol) from step 1 was dissolved in methanol (50 ml) and 10% palladium-carbon (50% water content, 313 mg) was added and stirred under hydrogen atmosphere at room temperature for 40 minutes. The catalyst in the reaction mixture was filtered through Celite, and the solvent was concentrated under reduced pressure to give 1.88 g of the title compound (quantitative).

[α] _D ²⁰ -30.5° (c 0.59, MeOH); ¹ H NMR (400 MHz, CD ₃ OD): δ: 1.70-1.79 (m, 1H), 1.87-2.11 (m, 2H), 2.00 (s, 3H), 2.27 (brd, J=15.0, 6.6 Hz, 1H), 3.15 (brd, J=12.0 Hz, 1H), 3.24 (d, J=12.0 Hz, 1H), 3.67-3.73 (m, 1H), 3.95 (d, J=7.2 Hz, 1H); MS m/z 243 [M+H] ⁺ .

Stage 3

(2S,5R)-N'-acetyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

To a solution of compound (1.87 g, 7.71 mmol) from step 2 in pyridine (35 ml) was added sulfur trioxide-pyridine complex (5.51 g) and the mixture was stirred at room temperature overnight. Methylene chloride is added to the reaction solution and filtered, then concentrated under reduced pressure. Toluene is added to the obtained residue, subjected to azeotropic distillation and concentrated to dryness. The mixture is added to a saturated aqueous solution of sodium hydrogen phosphate (200 ml), washed with ethyl acetate. Then, tetrabutylammonium hydrogen sulfate (3.17 g) and ethyl acetate are added, stirred for 10 minutes, and then the layers are separated. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride/acetone/triethylamine=49/49/2) to obtain 3.27 g of (2S,5R)-N'-acetyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide tetrabutylammonium.

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,01 (т, J=7,3 Гц, 12H), 1,45 (секст, J=7,3 Гц, 8H), 1,60-1,82 (м, 9H), 1,86-1,98 (м, 1H), 2,08 (с, 3H), 2,13-2,24 (м, 1H), 2,35 (шир.дд, J=15,2, 6,8 Гц, 1H), 3,17 (д, J=12,0 Гц, 1H), 3,23-3,40 (м, 8H), 3,37 (шир.д, J=12,0 Гц, 1H), 4,00 (д, J=7,6 Гц, 1H), 4,34 (шир.с, 1H), 7,92 (шир.с, 1H), 8,62 (шир.с, 1H); MS m/z 323 [M-Bu ₄ N+2H] ⁺ .

The above tetrabutylammonium salt was treated with DOWEX (Na form) and subjected to octadecyl silica gel column chromatography (water) to give 1.73 g of the title compound (65% yield).

[α] _D ²¹ -44.9° (c 0.55, H ₂ O); ¹ H NMR (400 MHz, D ₂ O): δ 1.64-1.75 (m, 1H), 1.75-1.91 (m, 1H), 1.91-2.02 (m, 1H), 1.95 (s, 3H), 2.05-2.14 (m, 1H), 3.09 (d, J=12.6 Hz, 1H), 3, 23 (brd, J=12.6 Hz, 1H), 4.05 (brd, J=7.2 Hz, 1H), 4.09 (brd, J=5.8, 3.0 Hz, 1H); MS m/z 323 [M-Na+2H] ⁺ ; Ma^x8, 2%. Na content 8.2%.

Example 22

(2S,5R)-7-oxo-N'-propanoyl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-7-oxo-N'-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of the carboxylic acid from Example 9 or 16 (6b, 354 mg, 1.28 mmol) in tetrahydrofuran (10 ml) was added triethylamine (0.216 ml) and isobutyl chloroformate (208 μl) under ice-cooling, followed by stirring at 0°C for 15 minutes. To the reaction solution was added a solution of propionyl hydrazide (161 mg, obtained by the method of Reference Example 3 and Reference Example 6) in tetrahydrofuran (3 ml) at 0° C., followed by stirring at room temperature for 1 hour, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-0/1) to obtain 425 mg of the title compound (96% yield).

[α] _D ²¹ +95.6° (c 0.46, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,20 (т, J=7,6 Гц, 3H), 1,56-1,66 (м, 1H), 1,91-2,05 (м, 2H), 2,25-2,40 (м, 3H), 3,09 (шир.д, J=12,0 Гц, 1H), 3,17 (д, J=12,0 Гц, 1H), 3,29-3,34 (м, 1H), 4,02 (д, J=7,6 Гц, 1H), 4,92 (д, J=11,4 Гц, 1H), 5,06 (д, J=11,4 Гц, 1H), 7,33-7,46 (м, 5H), 7,58 (шир.д, J=3,0 Гц, 1H), 8,50 (шир.д, J=3,0 Гц, 1H); MS m/z 347 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-7-oxo-N'-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

The compound (417 mg, 1.20 mmol) from the above step 1 was dissolved in methanol (10 ml), 10% palladium-carbon (50% water content, 110 mg) was added, stirred under hydrogen atmosphere at room temperature for 50 minutes. The catalyst in the reaction mixture was filtered through Celite, and the solvent was concentrated under reduced pressure to give 297 mg of the title compound (96% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.17 (t, J=7.6 Hz, 3H), 1.69-1.79 (m, 1H), 1.88-1.99 (m, 1H), 2.02-2.11 (m, 1H), 2.24-2.32 (m, 1H), 2.28 (sq., J=7.6 Hz) , 2H), 3.16 (bd, J=11.6 Hz, 1H), 3.26 (d, J=11.6 Hz, 1H), 3.68-3.72 (m, 1H), 3.95 (d, J=7.6 Hz, 1H); MS m/z 257 [M+H] ⁺ .

Stage 3

(2S,5R)-7-oxo-N'-propanoyl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

To a solution of the compound (296 mg, 1.15 mmol) from the above step 2 in pyridine (7.5 ml) was added sulfur trioxide-pyridine complex (843 mg) and the mixture was stirred at room temperature overnight. Methylene chloride was added to the reaction solution, followed by filtration and concentration under reduced pressure. Toluene was added to the residue, followed by azeotropic distillation. (2S,5R)-7-oxo-N'-propanoyl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide pyridinium is obtained, then neutralized with half saturated aqueous sodium bicarbonate solution and purified by octadecyl silica gel column chromatography to give 357 mg of the title compound (86% yield).

[α] _D ²¹ -46.7° (c 0.28, H ₂ O); ¹ H ЯМР (400 МГц, D ₂ O): δ 1,02 (т, J=7,6 Гц, 3H), 1,64-1,76 (м, 1H), 1,78-1,90 (м, 1H), 1,93-2,02 (м, 1H), 2,10 (шир.дд, J=15,6, 7,2 Гц, 1H), 2,22 (кв., J=7,6 Гц, 2H), 3,10 (д, J=12,0 Гц, 1H), 3,23 (шир.д, J=12,0 Гц, 1H), 4,04 (д, J=7,2 Гц, 1H), 4,07-4,12 (м, 1H); MS m/z 337 [M-Na+2H] ⁺ .

Example 23

(2S,5R)-N'-(2-methylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N'-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, from the carboxylic acid (6b, 363 mg, 1.31 mmol) from Example 9 or 16 and isobutyrohydrazide (190 mg), 440 mg of the title compound was obtained (93% yield).

[α] _D ²⁰ +86.6° (c 0.50, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,21 (д, J=6,8 Гц, 3H), 1,23 (д, J=6,8 Гц, 3H), 1,55-1,63 (м, 1H), 1,91-2,07 (м, 2H), 2,30-2,38 (м, 1H), 2,48 (септ., J=6,8 Гц, 1H), 3,09 (шир.д, J=12,0 Гц, 1H), 3,18 (д, J=12,0 Гц, 1H), 3,28-3,32 (м, 1H), 4,02 (шир.д, J=7,6 Гц, 1H), 4,92 (д, J=11,4 Гц, 1H), 5,06 (д, J=11,4 Hz, 1H), 7,34-7,53 (м, 6H), 8,47 (шир.д, J=3,6 Гц, 1H); MS m/z 361 [M+H] ⁺ .

Stage 2

(2S,5R)-6-hydroxy-N'-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, from the compound (426 mg, 1.18 mmol) of Step 1 above, 308 mg of the title compound was obtained (97% yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,16 (д, J=7,0 Гц, 3H), 1,17 (д, J=7,0 Гц, 3H), 1,70-1,79 (м, 1H), 1,87-1,99 (м, 1H), 2,02-2,12 (м, 1H), 2,27 (шир.дд, J=15,0, 7,0 Гц, 1H), 2,53 (септ., J=7,0 Гц, 1H), 3,16 (шир.д, J=12,0 Гц, 1H), 3,27 (д, J=12,0 Гц, 1H), 3,67-3,73 (м, 1H), 3,94 (шир.д, J=7,6 Гц, 1H); MS m/z 271 [M+H] ⁺ .

Stage 3

(2S,5R)-N'-(2-methylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Following the procedure of Example 22, (2S,5R)-N'-(2-methylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide was obtained from the compound (303 mg, 1.12 mmol) from the above step 2 and neutralized with saturated aqueous sodium bicarbonate, followed by purification by chromatography on an octade column. cilsilica gel to give 261 mg of the title compound (62% yield).

[a] _D ²⁰ -40.3° (c 0.94, H ₂ O); ¹ H ЯМР (400 МГц, D ₂ O): δ 1,01 (д, J=6,8 Гц, 6H), 1,62-1,73 (м, 1H), 1,76-1,88 (м, 1H), 1,91-2,00 (м, 1H), 2,08 (шир.дд, J=15,6, 6,8 Гц, 1H), 2,46 (септ., J=6,8 Гц, 1H), 3,09 (д, J=12,4 Гц, 1H), 3,21 (шир.д, J=12,4 Гц, 1H), 4,03 (д, J=7,6 Гц, 1H), 4,06-4,10 (м, 1H); MS m/z 351 [M-Na+2H] ⁺ .

Example 24

(2S,5R)-N'-(2,2-dimethylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N'-(2,2-dimethylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 18, from the carboxylic acid (6b, 400 mg, 1.44 mmol) from Example 9 or 16 and pivalic acid hydrazide (185 mg, 1.59 mmol), 506 mg of the title compound was obtained (93% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,14 (с, 9H), 1,49-1,54 (м, 1H), 1,77-1,88 (м, 2H), 2,14-2,19 (м, 1H), 2,93 (д, J=2,9, 1H), 3,11 (д, J=2,9, 1H), 3,18 (шир.с, 1H), 3,85 (д, J=1,8, 1H), 4,78 (д, J=2,8, 1H), 4,92 (д, J=2,8, 1H), 7,18-7,31 (м, 5H), 8,51 (с, 1H), 5,52 (с, 1H); MS m/z 375 [M+H] ⁺ .

Stage 2

(2S,5R)-N'-(2,2-Dimethylpropanoyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (quantitative yield).

Stage 3

(2S,5R)-N'-(2,2-dimethylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Using the same procedure as in Example 18, from the total amount of the compound from Step 2 above and purification by octadecyl silica gel column chromatography, 404 mg of the title compound was obtained (77% yield).

¹ H ЯМР (400 МГц, D ₂ O): δ 1,09 (с, 3H), 1,10 (с, 3H), 1,11 (д, J=0, 2, 3H), 1,67-1,73 (м, 1H), 1,74-1,88 (м, 1H), 1,95-1,99 (м, 1H), 2,08-2,14 (м, 1H), 3,14 (д, J=3,1, 1H), 3,22 (д, J=3,2, 1H), 3,70 (д, J=0,6, 1H), 4,04 (д, J=1,9, 1H), 4,10 (д, J=0,7, 1H); MS m/z 365 [M-Na+2H] ⁺ , 363 [M-Na] ^- .

Example 25

(2SR,5RS)-N'-acetyl-N'-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

(2SR,5RS)-N'-Acetyl-6-benzyloxy-N'-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, from (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (148 mg, 0.536 mmol) and N-methylacetohydrazide (64.0 mg, prepared from methylhydrazine and acetic anhydride) 221 mg of the title compound was obtained (88% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,59-1,73 (м, 1H), 1,88-2,10 (м, 2H), 2,02 (с, 1,8H), 2,17 (с, 1,2H), 2,31-2,39 (м, 1H), 2,69 (д, J=11,6 Гц, 0,6H), 3,07 (шир.д, J=11,6 Гц, 0,4H), 3,11-3,38 (м, 2H), 3,13 (с, 1, 8H), 3,30 (с, 1,2H), 4,01 (д, J=7,2 Гц, 1H), 4,92 (д, J=11,6 Гц, 1H), 5,06 (д, J=11,6 Гц, 0,4H), 5,07 (д, J=11,2 Гц, 0,6H), 7,31-7,53 (м, 5H), 8,49 (шир.с, 0,4H), 8,58 (шир.с, 0,6H); MS m/z 347 [M+H] ⁺ .

Stage 2

(2SR,5RS)-N'-Acetyl-6-hydroxy-N'-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, from the compound (216 mg, 0.624 mmol) of Step 1 above, 156 mg of the title compound was obtained (98% yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,74-1,83 (м, 1H), 1,89-2,04 (м, 1H), 2,01 (с, 2,5H), 2,06-2,14 (м, 1H), 2,17 (с, 0,5H), 2,22-2,32 (м, 1H), 2,96 (д, J=11,6 Гц, 0,8H), 3,06-3,24 (м, 1,2H), 3,11 (с, 2,5H), 3,28 (с, 0,5H), 3,68-3,74 (м, 1H), 3,96 (шир.д, J=7,6 Гц, 1H); MS m/z 257 [M+H] ⁺ .

Stage 3

(2SR,5RS)-N'-acetyl-N'-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Following the procedure of Example 22, a compound (150 mg, 0.585 mmol) was prepared from Step 2 above, (2SR,5RS)-N'-acetyl-N'-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide pyridinium, neutralized with saturated aqueous sodium bicarbonate, and then purified by column chromatography Dia ion HP21 (Mitsubishi Chemical) to give 148 mg of the title compound (71% yield).

¹ H ЯМР (400 МГц, D ₂ O): δ 1,67-1,80 (м, 1H), 1,80-2,04 (м, 2H), 1,93 (с, 2,4H), 2,05-2,16 (м, 1H), 2,09 (с, 0,6H), 2,98 (д, J=12,0 Гц, 0,8H), 3,00 (с, 2,4H), 3,11 (д, J=12,0 Гц, 0,2H), 3,18 (с, 0,6H), 3,20 (шир.д, J=12,0 Гц, 0,2H), 3,28 (шир.д, J=12,0 Гц, 0,8H), 4,01-4,15 (м, 2H); MS m/z 337 [M-Na+2H] ⁺ .

Example 26

(2SR,5RS)-N'-(Aminoacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Stage 1

tert-Butyl [2-(2-{[(2SR,5RS)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]carbamate

To a solution of (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (153 mg, 0.554 mmol) in tetrahydrofuran (3 ml) was added triethylamine (0.232 ml) and isobutyl chloroformate (89.1 μl) under ice-cooling, and the mixture was stirred at 0°C for 4 5 min. To the reaction solution was added a solution of tert-butyl 2-hydrazinyl-2-oxoethylcarbamate (129 mg, obtained by the method of Reference Example 5 and Reference Example 6) in tetrahydrofuran (3 ml) at 0°C, and stirred at room temperature for 2.5 hours, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3-0/10) to give 179 mg of the title compound (72% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,45 (с, 9H), 1,57-1,70 (м, 1H), 1,91-2,06 (м, 2H), 2,28-2,38 (м, 1H), 3,07 (шир.д, J=12,0 Гц, 1H), 3,12 (д, J=12,0 Гц, 1H), 3,29-3,34 (м, 1H), 3,88 (дд, J=16,3, 6,1 Гц, 1H), 3,92 (дд, J=16,3, 6,1 Гц, 1H), 4,02 (шир.д, J=7,2 Гц, 1H), 4,91 (д, J=11,2 Гц, 1H), 5,05 (д, J=11,2 Гц, 1H), 5,24 (шир.т, J=6,1 Гц, 1H), 7,34-7,46 (м, 5H), 8,42 (шир.с, 1H), 8,53 (шир.с, 1H); MS m/z 448 [M+H] ⁺ .

Stage 2

tert-butyl [2-(2-{[(2SR,5RS)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]carbamate

The compound (176 mg, 0.394 mmol) from the above step 1 was dissolved in methanol (4 ml), 10% palladium-carbon (50% water content, 42.4 mg) was added and stirred under hydrogen atmosphere at room temperature for 40 minutes. The catalyst from the reaction mixture was filtered through Celite, the solvent was concentrated under reduced pressure to give 140 mg of the title compound (quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.45 (s, 9H), 1.69-1.79 (m, 1H), 1.87-2.00 (m, 1H), 2.01-2.11 (m, 1H), 2.27 (brd, J=15.0, 6.6 Hz, 1H), 3.16 (brd, J =12.0 Hz, 1H), 3.24 (d, J=12.0 Hz, 1H), 3.67-3.73 (m, 1H), 3.81 (s, 2H), 3.95 (brd, J=7.2 Hz, 1H); MS m/z 358 [M+H] ⁺ .

Stage 3

(2SR,5RS)-N'-(Aminoacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of the compound (137 mg, 0.382 mmol) from the above step 2 in pyridine (4 ml) was added sulfur trioxide-pyridine complex (276 mg) and the mixture was stirred at room temperature overnight. Methylene chloride was added to the reaction mixture, followed by filtration and concentration under reduced pressure. Toluene was added to the resulting residue, followed by azeotropic distillation. 405 mg of tert-butyl [2-(2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]pyridinium carbamate is obtained. MS m/z 438 [M-C ₅ H ₅ N+H] ⁺ .

The total amount of the pyridinium salt was dissolved in methylene chloride (5 ml) and trifluoroacetic acid (1.7 ml) was added, the mixture was stirred at room temperature for 3.5 hours. The reaction solution is concentrated under reduced pressure. The residue obtained is washed with diethyl ether and adjusted to pH 7 with aqueous sodium bicarbonate solution and lyophilized. The resulting crude product was purified on Sepabeads SP207 (Mitsubishi Chemical) (acetonitrile/water=0/100-10/90). After lyophilization, 42.6 mg of the title compound are obtained (2 steps, 33% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.63-1.74 (m, 1H), 1.78-1.89 (m, 1H), 1.92-2.02 (m, 1H), 2.05-2.14 (m, 1H), 3.08 (d, J=12.4 Hz, 1H), 3.23 (brd, J=12, 4 Hz, 1H), 4.06 (brd, J=6.4 Hz, 1H), 4.07-4.12 (m, 1H); MS m/z 338 [M+H] ⁺ .

Example 27

(2S,5R)-N'-(3-Aminopropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Stage 1

tert-Butyl [3-(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-3-oxopropyl]carbamate

To a solution of the carboxylic acid (6b, 390 mg, 1.41 mmol) from example 9 or 16 in methylene chloride (14.1 ml) was added triethylamine (393 μl), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (406 mg), 1-hydroxybenzotriazole monohydrate (324.6 mg) and tert-butyl (3-hydrazinyl-3 -oxopropyl)carbamate (430.8 mg, obtained by the method of Reference Example 2), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel (ethyl acetate) column chromatography to obtain 347.3 mg of the title compound (53.3% yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,32 (с, 9H), 1,55-1,63 (м, 1H), 1,75-1,91 (м, 2H), 2,11-2,17 (м, 1H), 2,31-2,34 (т, J=6,4 Гц, 2H), 2,92-2,95 (шир.д, J=11,6 Гц, 1H), 3,09-3,12 (д, J=11,6 Гц, 1H), 3,20-3,26 (т, J=6,4 Гц, 2H), 3,47 (шир.с, 1H), 3,86-3,88 (д, J=7,6 Гц, 1H), 4,82-4,85 (д, J=11,2 Гц, 1H), 4,89-4,92 (д, J=11,2 Гц, 1H), 7,27-7,31 (м, 3H), 7,35-7,38 (м, 2H); MS m/z 462 [M+H] ⁺ .

Stage 2

tert-Butyl [3-(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-3-oxopropyl]carbamate

The total amount of the compound from the above step 1 was dissolved in methanol (7.5 ml), 10% palladium-carbon (water content 50%, 69 mg) was added and stirred under hydrogen atmosphere at room temperature for 1 hour. The catalyst from the reaction mixture was filtered through Celite, and the solvent was concentrated under reduced pressure to give the title compound (yield quantitative).

Stage 3

(2S,5R)-N'-(3-Aminopropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of the total compound from the above Step 2 in pyridine (7.5 ml) was added sulfur trioxide-pyridine complex (598.4 mg) and the mixture was stirred at room temperature overnight. Methylene chloride is added to the reaction mixture, filtered and concentrated under reduced pressure. Toluene was added to the resulting residue, followed by azeotropic distillation. tert-Butyl [3-(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-3-oxopropyl]pyridinium carbamate is obtained (quantitative yield). MS m/z 450 [M-C ₅ H ₅ N-H] ^- .

The total pyridinium salt was deprotected with trifluoroacetic acid and purified by silica gel column chromatography to give 191 mg of the title compound (72.3% yield).

¹ H ЯМР (400 МГц, D ₂ O): δ 1,62-1,70 (м, 1H), 1,76-1,86 (м, 1H), 1,92-1,95 (м, 1H), 2,04-2,09 (м, 1H), 2,60-2,63 (т, J=6,8 Гц, 2H), 3,04-3,07 (д, J=12,0 Гц, 1H), 3,13-3,16 (т, J=6,8 Гц, 2H), 3,18-3,22 (д, J=11,6 Гц, 1H), 4,02-4,03 (д, J=7,2 Гц, 1H), 4,06 (шир.с, 1H); MS m/z 352 [M+H] ⁺ .

Example 28

(2S,5R)-N'-[(4-Aminophenyl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Stage 1

tert-Butyl

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and tert-butyl (4-(2-hydrazinyl-2-oxoethyl)phenyl)carbamate (682.6 mg, prepared by the method of Reference Example 5 and Reference Example 6), 550.8 mg of the title compound was obtained (74.6% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,45 (с, 9H), 1,56-1,64 (м, 1H), 1,86-1,97 (м, 2H), 2,27-2,33 (м, 1H), 3,03-3,06 (шир.д, J=11,6 Гц, 1H), 3,12-3,15 (д, J=11,6 Гц, 1H), 3,27 (шир.с, 1H), 3,75 (с, 2H), 3,96-3,98 (д, J=6,8 Гц, 1H), 4,87-4,89 (д, J=11,2 Гц, 1H), 5,01-5,04 (д, J=11,6 Гц, 1H), 6,47 (с, 1H), 7,21-7,24 (шир.д, J=10,8 Гц, 2H), 7,32-7,49 (м, 7H), 8,47 (шир.с, 1H); MS m/z 524 [M+H] ⁺ .

Stage 2

tert-Butyl 4-{[2-(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]phenyl}carbamate

Following the procedure of Example 17, 425 mg of the title compound was obtained from the total amount of the compound from Step 1 above (93.2% yield). MS m/z 434 [M+H] ⁺ .

Stage 3

(2S,5R)-N'-[(4-Aminophenyl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, from the total amount of the compound from Step 2, tetrabutylammonium tert-butyl 4-{[2-(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]phenyl}carbamate is obtained (quantitative yield). MS m/z 512 [M-Bu ₄ N] ^- .

The total pyridinium salt was deprotected with trifluoroacetic acid and purified by silica gel column chromatography to give 226 mg of the title compound (55.8% yield).

¹ H ЯМР (400 МГц, D ₂ O): δ 1,61-1,69 (м, 1H), 1,74-1,84 (м, 1H), 1,90-1,94 (м, 1H), 2,03-2,08 (м, 1H), 3,03-3,06 (д, J=12,0 Гц, 1H), 3,16-3,19 (д, J=12,0 Гц, 1H), 3,43 (шир.с, 2H), 3,99-4,01 (д, J=7,6 Гц, 1H), 4,05 (шир.с, 1H), 6,67-6,69 (д, J=8,4 Гц, 1H), 7,00-7,02 (д, J=8,4 Гц, 1H); MS m/z 412 [MH] ^- .

Example 29

(2S,5R)-N'-(Methoxyacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N'-(methoxyacetyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and 2-methoxyacetohydrazide (220.7 mg), 397.1 mg of the title compound was obtained (77.7% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,50-1,59 (м, 1H), 1,85-1,94 (м, 2H), 2,26-2,33 (м, 1H), 3,01-3,04 (шир.д, J=12,4 Гц, 1H), 3,06-3,09 (д, J=12,0 Гц, 1H), 3,24 (с, 1H), 3,39 (с, 3H), 3,97-4,00 (м, 3H), 4,83-4,86 (д, J=11,6 Гц, 1H), 4,97-5,00 (д, J=11,6 Гц, 1H), 7,27-7,37 (м, 5H), 8,22 (м, 1H), 8,44 (м, 1H); MS m/z 363 [M+H] ⁺ .

Stage 2

(2S,5R)-6-hydroxy-N'-(methoxyacetyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative). MS m/z 273 [M+H] ⁺ .

Stage 3

(2S,5R)-N'-(methoxyacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Following the procedure of Example 22, pyridinium (2S,5R)-N'-(methoxyacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide pyridinium was obtained from the total amount of the compound from step 2 and neutralized with saturated aqueous sodium bicarbonate. Purification by Sepabeads SP207 (Mitsubishi Chemical) column chromatography gave 134.4 mg of the title compound (32.7% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.65-1.73 (m, 1H), 1.77-1.87 (m, 1H), 1.93-1.96 (m, 1H), 2.05-2.11 (m, 1H), 3.06-3.09 (brd, J=12.0 Hz, 1H), 3.19-3, 22 (d, J=12.8 Hz, 1H), 3.31 (s, 3H), 3.97-4.04 (m, 3H), 4.07 (s, 1H); MS m/z 353 [M-Na+2H] ⁺ .

Example 30

(2SR,5RS)-N'-benzoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

(2SR,5RS)-N'-Benzoyl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Triethylamine (231 µl) and 2-chloro-1-methylpyridin-1-ium iodide (138 .7 mg), then the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate aqueous solution was added to the reaction solution, extracted with chloroform. The organic layer is dried over sodium sulfate and then concentrated. The resulting crude product was purified by silica gel column chromatography to give 123.0 mg of the title compound (86% yield). MS m/z 395 [M+H] ⁺ .

Stage 2

(2SR,5RS)-N'-Benzoyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of the total amount from the above Step 1 in methanol (3 ml) was added 50% palladium-carbon (water content 50%, 20 mg) and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The catalyst from the reaction mixture is filtered through a PTFE membrane, then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give 30 mg of the title compound (32% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.76-1.80 (m, 1H), 1.94-2.00 (m, 1H), 2.29-2.31 (m, 1H), 3.20-3.38 (m, 1H), 3.73 (br s, 1H), 4.02 (d, J=1.9, 1H), 7 .47-7.90 (m, 1H); m/z 305 [M+H]+.

Stage 3

(2SR,5RS)-N'-benzoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

To a solution of the total amount from the above step 2 in methylene chloride (2.0 ml) was added 2,6-lutidine (145 μl) and sulfur trioxide-pyridine complex (63 mg) and the mixture was stirred at room temperature overnight. Chloroform was added to the reaction solution, followed by liquid separation with water. The aqueous layer was concentrated to 1 ml under reduced pressure, then purified by octadecyl silica gel column chromatography. The resulting (2SR,5RS)-N'-benzoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide pyridinium was subjected to a salt exchange reaction using Dowex-Na type to give 4 mg of the title compound (37% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.73-1.75 (m, 1H), 1.82-1.95 (m, 1H), 2.10-2.15 (m, 1H), 3.16 (d, J=3.2, 1H), 3.26 (d, J=3.0, 1H), 4.09 (m, 2H), 7.3 9-7.54 (m, 5H); MS m/z 385 [M-Na+2H] ⁺ .

Example 31

(2S,5R)-N'-(4-Aminobenzoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Stage 1

tert-Butyl

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and tert-butyl (4-(hydrazinecarbonyl)phenyl)carbamate (653 mg, prepared according to the procedure of Reference Example 5 and Reference Example 6), 689.5 mg of the title compound was obtained (96.0% yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,52 (с, 9H), 1,68-1,75 (м, 1H), 1,89-2,00 (м, 2H), 2,24-2,30 (м, 1H), 3,07-3,10 (д, J=10,8 Гц, 1H), 3,30 (м, 1H), 3,58 (шир.с, 1H), 4,02-4,04 (д, J=7,6 Гц, 1H), 4,93-4,59 (д, J=11,6 Гц, 1H), 5,00-5,03 (д, J=11,6 Гц, 1H), 7,33-7,41 (м, 3H), 7,46-7,48 (м, 2H), 7,51 (д, J=8,8 Гц, 2H), 7,80(д, J=8,8 Гц, 2H); MS m/z 510 [M+H] ⁺ .

Stage 2

tert-Butyl {4-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]phenyl}carbamate

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative). MS m/z 420 [M+H] ⁺ .

Stage 3

(2S,5R)-N'-(4-Aminobenzoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, tetrabutylammonium tert-butyl {4-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]phenyl}carbamate tetrabutylammonium was obtained from the total amount of the compound from step 2 (quantitative yield). MS m/z 498 [M-Bu ₄ N] ^- .

The total tetrabutylammonium salt was deprotected with trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 127.4 mg of the title compound (23.6% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.65-1.73 (m, 1H), 1.78-1.88 (m, 1H), 1.93-1.97 (m, 1H), 2.08-2.13 (m, 1H), 3.14-3.17 (d, J=12.0 Hz, 1H), 3.26-3.26 (d, J=12.0 Hz, 1H), 4.07 (m, 2H), 6.69-6.71 (d, J=8.4 Hz, 2H), 7.52-7.54 (d, J=8.4 Hz, 2H); MS m/z 400 [M+H] ⁺ .

Example 32

(2SR,5RS)-N'-(4-(Aminomethyl)benzoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Stage 1

tert-Butyl {4-[(2-{[(2SR,5RS)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]benzyl}carbamate

Following the procedure of Example 27, from (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (200 mg, 0.724 mmol) and tert-butyl 4-(hydrazinecarbonyl)benzylcarbamate (226 mg, obtained according to the procedure of Reference Example 5 and Reference Example 6), 288 .7 mg of the title compound (76.1% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,49 (с, 9H), 1,62 (м, 1H), 1,95-2,05 (м, 2H), 2,34-2,39 (м, 1H), 3,14 (шир.д, J=11,6 Гц, 1H), 3,20 (д, J=1 1,6 Гц, 1H), 3,34 (с, 1H), 4,07 (д, J=6,8 Гц, 1H), 4,36 (шир.д, J=5,6 Гц, 2H), 4,92 (д, J=11,6 Гц, 1H), 5,06 (д, J=11,4 Гц, 1H), 7,34-7,52 (м, 7H), 7,83 (д, J=8,4 Гц, 2H); MS m/z 524 [M+H] ⁺ .

Stage 2

tert-Butyl {4-[(2-{[(2SR,5RS)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]benzyl}carbamate

Following the procedure of Example 17, 216.1 mg of the title compound was obtained from the total amount of the compound from Step 1 (90.4% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.45 (s, 9H), 1.74-1.82 (m, 1H), 1.91-2.03 (m, 1H), 2.09-2.20 (m, 1H), 2.29-2.34 (m, 1H), 3.20-3.30 (m, 2H), 3.74 (s, 1H), 4.02 (d, J=7.6 Hz, 1H), 4.29 (br s, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H);

Stage 3

(2SR,5RS)-N'-(4-(Aminomethyl)benzoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 26, from the total amount of the compound from step 2, tert-butyl {4-[(2-{[2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]benzyl}pyridinium carbamate was obtained (quantitative yield).

¹H NMR (400 MHz, D₂O): δ 1.29 (s, 9H), 1.74-1.76 (m, 1H), 1.81-1.89 (m, 1H), 1.96-1.91 (m, 1H), 2.11-2.15 (m, 1H), 3.18 (d, J=12.8 Hz, 1H), 3.27 (d, J=12.8 Hz, 1H), 3.59 (s, 1H), 4.12 (d, J=4.4 Hz, 1H), 4.19 (br s, 2H), 7.32 (d, J=7.6 Hz, 2H), 7.68 (d, J=7.6 Hz, 2H), 7.91-8.63 (m, 5H):

The total pyridine salt was deprotected with trifluoroacetic acid and purified by Diaion HP21 (Mitsubishi Chemical) to give 100.3 mg of the title compound (48.7% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.80-1.88 (m, 1H), 1.94-2.00 (m, 1H), 2.08 (m, 1H), 2.24-2.28 (m, 1H), 3.30 (d, J=12.4 Hz, 1H), 3.40 (d, J=1 2.0 Hz, 1H ), 4.20-4.24 (m, 4H), 7.62 (d, J=8.0 Hz, 2H), 7.93 (d, J=8.0 Hz, 2H); MS m/z 414 [M+H] ⁺ .

Example 33

(2SR,5RS)-7-oxo-N-(2-oxopyrrolidin-1-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2SR,5RS)-6-benzyloxy-7-oxo-N-(2-oxopyrrolidin-1-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 17, from (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (164 mg, 0.594 mmol) and 1-aminopyrrolidin-2-one hydrochloride (101 mg), 128 mg of the title compound was obtained (60% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,57-1,70 (м, 1H), 1,88-2,22 (м, 4H), 2,30-2,52 (м, 3H), 3,09 (шир.д, J=12,0 Гц, 1H), 3,22 (д, J=12,0 Гц, 1H), 3,30-3,35 (м, 1H), 3,46 (ддд, J=8,5, 8,5, 4,8 Гц, 1H), 3,73 (кв., J=7,7 Гц, 1H), 4,02 (шир.д, J=7,6 Гц, 1H), 4,92 (д, J=11,2 Гц, 1H), 5,06 (д, J=11,2 Гц, 1H), 7,35-7,46 (м, 5H), 8,34 (шир.с, 1H); MS m/z 359 [M+H] ⁺ .

Stage 2

(2SR,5RS)-6-hydroxy-7-oxo-N-(2-oxopyrrolidin-1-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 17, from the compound (126 mg, 0.352 mmol) of Step 1 above, the title compound was obtained (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.70-1.80 (m, 1H), 1.88-2.00 (m, 1H), 2.02-2.19 (m, 3H), 2.27 (brd, J=15.0, 7.0 Hz, 1H), 2.40-2.47 (m, 2H), 3.16 ( brd, J=11.6 Hz, 1H), 3.21 (d, J=11.6 Hz, 1H), 3.52-3.65 (m, 2H), 3.68-3.73 (m, 1H), 3.96 (d, J=7.6 Hz, 1H); MS m/z 269 [M+H] ⁺

Stage 3

(2SR,5RS)-7-oxo-N-(2-oxopyrrolidin-1-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

To a solution of the total compound from step 2 in pyridine (3.5 ml) was added sulfur trioxide-pyridine complex (248 mg) and the mixture was stirred at room temperature overnight. Methylene chloride was added to the reaction mixture, filtered, and then concentrated under reduced pressure. Toluene was added to the resulting residue, followed by azeotropic distillation. 178 mg of (2SR,5RS)-7-oxo-N-(2-oxopyrrolidin-1-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium are obtained. MS m/z 349 [M-C ₅ H ₅ NH] ⁺ .

The total amount of the pyridinium salt obtained above was added to water and a saturated sodium bicarbonate aqueous solution and adjusted to pH 7, followed by lyophilization. The resulting crude product was purified with Diaion HP21 (Mitsubishi Chemical) (acetonitrile/water=100/0-90/10), followed by lyophilization, to give 103 mg of the title compound (2 steps, 79% yield).

¹ H ЯМР (400 МГц, D ₂ O): δ 1,65-1,74 (м, 1H), 1,77-1,89 (м, 1H), 1,92-2,14 (м, 2H), 2,03 (кв., J=7,6 Гц, 2H), 2,38 (т, J=7,6 Гц, 2H), 3,06 (д, J=12,0 Гц, 1H), 3,23 (шир.д, J=12,0 Гц, 1H), 3,49 (т, J=7,6 Гц, 2H), 4,05 (шир.д, J=6,8 Гц, 1H), 4,08 (шир.дд, J=5,8, 3,0 Гц, 1H); MS m/z 349 [M-Na+2H] ⁺ .

Example 34

(2S,5R)-7-oxo-6-(sulfooxy)-N'-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

(2S,5R)-6-Benzyloxy-7-oxo N'-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and tetrahydro-2H-pyran-4-carbohydrazide (952 mg) described in Reference Example 2, 309.8 mg of the title compound was obtained (54.5% yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,69-2,00 (м, 7H), 2,20-2,25 (м, 1H), 2,49-2,57 (м, 1H), 3,02 (шир.д, J=12,0 Гц, 1H), 3,20 (д, J=12,0 Гц, 1H), 3,41-3,47 (м, 2H), 3,56 (с, 1H), 3,94-3,97 (м, 3H), 4,91-4,94 (д, J=11,2 Гц, 1H), 4,98-5,01 (д, J=11,2 Гц, 1H), 7,34-7,47 (м, 5H); MS m/z 403 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-7-oxo-N'-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative). MS m/z 313 [M+H] ⁺ .

Stage 3

(2S,5R)-7-oxo-6-(sulfooxy)-N'-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Following the procedure of Example 22, (2S,5R)-7-oxo-6-(sulfooxy)-N'-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide pyridinium was obtained from the total amount of the compound from step 2 and neutralized with saturated aqueous sodium bicarbonate, then purified by Sepabeads column chromatography SP207 (Mitsubishi Chemical) to give 198.9 mg of the title compound (62.4% yield).

¹ H ЯМР (400 МГц, D ₂ O): δ 1,57-1,66 (м, 5H), 1,76-1,86(м, 1H), 1,93 (м, 1H), 2,05-2,09 (м, 1H), 2,52-2,56 (м, 1H), 3,07-3,10 (шир.д, J=12,0 Гц, 1H), 3,20-3,23 (д, J=12,0 Гц, 1H), 3,36-3,41 (м, 2H), 3,86-3,89 (д, J=10,0 Гц, 2H), 4,02-4,04 (J=7,6 Гц, 1H), 4,07(с, 1H); MS m/z 393 [M-Na+2H] ⁺ .

Example 35

(2S,5R)-7-Oxo-N'-(piperidin-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl 4-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (642 mg, prepared according to the procedure of Reference Example 5 and Reference Example 6), 552.7 mg of the title compound was obtained (78.1% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,42 (с, 9H), 1,60-1,71 (м, 3H), 1,77-1,92 (м, 2H), 1,96-2,02 (м, 2H), 2,28-2,36 (м, 2H), 2,72-2,78 (дд, J=12 Гц, 2H), 3,06-3,09 (шир.д, J=12,0 Гц, 1H), 3,14-3,17 (д, J=11,6 Гц, 1H), 3,28 (шир.с, 1H), 4,00-4,01 (д, J=7,2 Гц, 1H), 4,07-4,12 (дд, J=14,4 Гц, 2H), 4,87-4,90 (д, 11,2 Гц, 1H), 5,02-5,04 (д, J=11,6 Гц, 1H), 7,23-7,41 (м, 5H), 7,57 (шир.с, 1H), 8,58 (шир.с, 1H); MS m/z 502 [M+H] ⁺ .

Stage 2

tert-Butyl 4-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following the procedure of Example 17, 423.8 mg of the title compound was obtained from the total amount of the compound from Step 1 (93.6% yield). MS m/z 412 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N'-(piperidin-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 26, from the total amount of the compound from step 2, tert-butyl 4-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-pyridinium carboxylate is obtained (quantitative yield). MS m/z 492 [M-C ₅ H ₅ NH] ⁺ .

The total pyridine salt was deprotected with trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 150 mg of the title compound (37.2% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.62-2.10 (m, 8H), 2.57-2.63 (m, 1H), 2.91-2.96 (dd, J=11.6, 12.8 Hz, 2H), 3.05-3.08 (d, J=12.4 Hz, 1H), 3.19-3.22 (d , J=12.0 Hz, 1H), 3.33-3.36 (d, J=13.2 Hz, 2H), 4.01-4.03 (d, J=7.6 Hz, 1H), 4.07 (br s, 1H); MS m/z 392 [M+H] ⁺ .

Example 36

(2S,5R)-7-Oxo-N'-[(2S)-piperidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Stage 1

tert-Butyl (2S)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and (S)-tert-butyl 2-(hydrazinecarbonyl)piperidine-1-carboxylate (634 mg, prepared according to the procedure of Reference Example 5 and Reference Example 6), 567 mg of the title compound was obtained (80% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.35-1.72 (m, 6H), 1.49 (s, 9H), 1.90-2.10 (m, 2H), 2.16-2.40 (m, 2H), 2.98-3.37 (m, 5H), 3.96-4.08 (m, 2H), 4.85 (br s, 1H), 4.92 (d, J=11.2 Hz, 1H), 5.06 (d, J=11.2 Hz, 1H), 7.33-7.47 (m, 5H), 8.30 (br s, 1H); MS m/z 502 [M+H] ⁺ .

Stage 2

tert-Butyl (2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative). MS m/z 410 [M-N] ^- .

Stage 3

(2S,5R)-7-Oxo-N'-[(2S)-piperidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of the total amount of the compound from the above step 2 in pyridine (11.3 ml) was added sulfur trioxide-pyridine complex (899 mg) and the mixture was stirred at room temperature overnight. Pyridine was added to the reaction mixture, filtered, and then concentrated under reduced pressure. Toluene is added to the resulting residue, then subjected to azeotropic distillation and concentrated to dryness. An aqueous solution of sodium dihydrogen phosphate (15 ml) was added, the aqueous layer was washed with ethyl acetate and then with tetrabutylammonium hydrogen sulfate (421 mg) and ethyl acetate (30 ml), and the mixture was stirred for 10 minutes. The aqueous layer was extracted with ethyl acetate, then the resulting organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1 -tetrabutylammonium carboxylate (quantitative yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.01 (t, J=7.4 Hz, 12H), 1.30-1.75 (m, 23H), 1.44 (s, 9H), 1.84-1.98 (m, 2H), 2.13-2.42 (m, 2H), 2.97-3.12 (m, 1H), 3.20-3.46(m, 10H), 3.80-4.15(m, 2H), 4.36(brs, 1H), 4.86(brs, 1H), 8.43(brs, 1H); MS m/z 490 [M-Bu ₄ N] ^- .

The total amount of the obtained tetrabutylammonium salt was dissolved in methylene chloride (5.7 ml), and trifluoroacetic acid (5.7 ml) was added under ice-cooling, and the mixture was stirred at 0° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, adjusted to pH 7 with an aqueous sodium bicarbonate solution, purified by octadecyl silica gel (water) column chromatography, and lyophilized. 104 mg of the title compound are obtained (3 steps, 23% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.42-2.17 (m, 10H), 2.83-2.97 (m, 1H), 3.06 (d, J=12.0 Hz, 1H), 3.23 (brd, J=12.0 Hz, 1H), 3.34 (brd, J=12.0 Hz, 1H), 3.8 1 (dd, J=12.0, 3.0 Hz, 1H), 3.99-4.13 (m, 2H); MS m/z 392 [M+H] ⁺ .

Example 37

(2S,5R)-7-Oxo-N'-[(2R)-piperidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Stage 1

tert-Butyl (2R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and (R)-tert-butyl 2-(hydrazinecarbonyl)piperidine-1-carboxylate (630 mg, prepared as in Reference Example; addition of hydrogen) to give 648 mg of the title compound (92% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.35-1.72 (m, 6H), 1.49 (s, 9H), 1.90-2.06 (m, 2H), 2.15-2.40 (m, 2H), 2.80-3.32 (m, 5H), 3.94-4.07 (m, 2H), 4.86 (br s, 1H), 4.92 (d, J=11.4 Hz, 1H), 5.06 (d, J=11.4 Hz, 1H), 7.34-7.45 (m, 5H), 8.40 (br s, 1H); MS m/z 502 [M+H] ⁺ .

Stage 2

tert-Butyl (2R)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.35-1.60 (m, 2H), 1.46 (s, 9H), 1.60-1.82 (m, 4H), 1.87-2.15 (m, 2H), 2.17-2.34 (m, 2H), 3.10-3.20 (m, 2H), 3.24 -3.36 (m, 2H), 3.67-3.73 (m, 1H), 3.91-4.05 (m, 2H); MS m/z 412 [M + H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N'-[(2R)-piperidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, from the total amount of the compound from step 2, tetrabutylammonium tert-butyl-1-carboxylate was obtained (quantitative yield). MS m/z 490 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was deprotected with trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 158.8 mg of the title compound (3 steps, 31% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.42-1.88 (m, 7H), 1.91-2.01 (m, 1H), 2.03-2.17 (m, 2H), 2.88-2.98 (m, 1H), 3.05 (d, J=12.0 Hz, 1H), 3.22 (brd, J=12, 0 Hz, 1H), 3.35 (brd, J=12.8 Hz, 1H), 3.89 (dd, J=12.0, 3.2 Hz, 1H), 3.99-4.13 (m, 2H); MS m/z 392 [M+H] ⁺ .

Example 38

(2S,5R)-7-Oxo-N'-[(2S)-pyrrolidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Stage 1

tert-Butyl (2S)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and (S)-tert-butyl 2-(hydrazine-carbonyl)pyrrolidine-1-carboxylate (573 mg) described in Reference Example 6, 555 mg of the title compound was obtained (80.1% yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,41 (с, 9H), 1,70-1,73 (м, 1H), 1,86-2,09 (м, 5H), 2,13-2,28 (м, 2H), 3,01-3,04 (шир.д, J=11,6 Гц, 1H), 3,15-3,21 (т, J=11,6 Гц, 1H), 3,31-3,40 (м, 1H), 3,48-3,56 (м, 2H), 3,94-3,96 (д, J=7,2 Гц, 1H), 4,23-4,26 (д, J=7,2 Гц, 1H), 4,91-4,94 (д, J=11,6 Гц, 1H), 4,98-5,01 (д, J=11,6 Гц, 1H), 7,34-7,40 (м, 3H), 7,45-7,47 (м, 2H); MS m/z 488 [M+H] ⁺ .

Stage 2

tert-Butyl (2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.41 (s, 9H), 1.70-1.75 (m, 1H), 1.82-2.04 (m, 5H), 2.18-2.27 (m, 2H), 3.09-3.21 (m, 2H), 3.32-3.37 (m, 1H), 3.46 -3.51 (m, 1H), 3.65 (br s, 1H), 3.89-3.91 (d, J 7.6 Hz, 1H), 4.20-4.23 (m, 1H); MS m/z 398 [M+H] ⁺ .

Stage 3

(2S,5R)-7-oxo-N'-[(2S)-pyrrolidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, 782.1 mg of tert-butyl (2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate tetrabutylammonium (yield 96.3 %). MS m/z 476 [M-Bu ₄ N] ^- .

The total amount of the tetrabutylammonium salt obtained above was deprotected with trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 143.8 mg of the title compound (35.2% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.66-1.85 (m, 6H), 2.04-2.16 (m, 2H), 2.99-3.30 (m, 4H), 3.87-4.18 (m, 3H); MS m/z 378 [M+H] ⁺ .

Example 39

(2S,5R)-7-oxo-N'-[(2R)-pyrrolidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Stage 1

tert-Butyl (2R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (R)-tert-butyl 2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (573 mg, prepared by the procedure of Reference Example 5 and Reference Example 6), to give 624.3 mg of the title compound (90.8% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,40 (с, 9H), 1,52-1,57 (м, 1H), 1,81-1,97 (м, 5H), 2,25-2,56 (м, 2H), 3,01-3,07 (м, 2H), 3,17 (шир.с, 1H), 3,17-3,42 (м, 2H), 3,94-3,96 (д, J=7,2 Гц, 1H), 4,30 (м, 1H), 4,82-4,85 (д, J=11,2 Гц, 1H), 4,97-5,00 (д, J=11,2 Гц, 1H), 7,27-7,37 (м, 5H), 8,37 (шир.с, 1H), 8,94 (шир.с, 1H); MS m/z 488 [M+H] ⁺ .

Stage 2

tert-Butyl (2R)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,40 (с, 9H), 1,52-1,57 (м, 1H), 1,81-1,97 (м, 5H), 2,25-2,56 (м, 2H), 3,01-3,07 (м, 2H), 3,17 (шир.с, 1H), 3,17-3,42 (м, 2H), 3,94-3,96 (д, J=7,2 Гц, 1H), 4,30 (м, 1H), 4,82-4,85 (д, J=11,2 Гц, 1H), 4,97-5,00 (д, J=11,2 Гц, 1H), 7,27-7,37 (м, 5H), 8,37 (шир.с, 1H), 8,94 (шир.с, 1H); MS m/z 398 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N'-[(2R)-pyrrolidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Using the procedure of Example 17, from the total amount of the compound from step 2, tetrabutylammonium tert-butyl-1-carboxylate was obtained (quantitative yield). Then, the total tetrabutylammonium salt was subjected to a deprotection reaction with trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 132.5 mg of the title compound (27.4% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.68-1.71 (m, 1H), 1.76-1.88 (m, 4H), 1.92 (m, 1H), 2.04-2.18 (m, 2H), 2.99-3.02 (d, J=12.0 Hz, 1H), 3.04-3.21 (m, 3 H), 3.92-4.00 (m, 2H), 4.06 (br s, 1H); MS m/z 378 [M+H] ⁺ .

Example 40

(2S,5R)-N'-{[(2S,4R)-4-Cyclopropylmethylpiperidin-2-yl]carbonyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Stage 1

tert-Butyl (2S,4R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazobicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-4-cyclopropylmethylpiperidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and (2S,4R)-tert-butyl 4-(cyclopropylmethyl)-2-(hydrazinecarbonyl)piperidine-1-carboxylate (595 mg, obtained by the method of Reference Example 5 and Reference Example 6), to give 707.6 mg of the title ke compound (yield 90.3%).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 0,01 (м, 2H), 0,40-0,42 (м, 2H), 0,66 (м, 1H), 1,18-1,68 (м, 8H), 1,46 (с, 9H), 1,82-2,17 (м, 2H), 2,30-2,34 (м, 1H), 3,10-3,18 (м, 2H), 3,29-3,33 (м, 2H), 3,65 (м, 1H), 4,01-4,02 (д, J=7,2 Гц, 1H), 4,40-4,44 (м, 1H), 4,89-4,92 (д, J=11,6 Гц, 1H), 5,04-5,07 (д, J=11,2 Гц, 1H), 7,26-7,44 (м, 5H), 8,02 (шир.с, 1H), 8,39 (шир.с, 1H); MS m/z 556 [M+H] ⁺ .

Stage 2

tert-Butyl (2S,4R)-4-cyclopropylmethyl-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 0.01 (m, 2H), 0.38 (m, 2H), 0.67 (m, 1H), 1.21-1.24 (m, 2H), 1.42 (s, 9H), 1.70-1.94 (m, 6H), 2.06-2.10 (m, 2H), 2, 19-2.25 (m, 1H), 3.10-3.26 (m, 4H), 3.66 (m, 1H), 3.90-3.92 (d, J=7.2 Hz, 1H), 4.25 (m, 1H); MS m/z 466 [M+H] ⁺ .

Stage 3

(2S,5R)-N'-{[(2S,4R)-4-Cyclopropylmethylpiperidin-2-yl]carbonyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, from the total amount of the compound from step 2, 993.5 mg of tert-butyl (2S,4R)-4-cyclopropylmethyl-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate tetrabutylam monium (yield 98.9%). MS m/z 544 [M-Bu ₄ N] ^- .

The total amount of the tetrabutylammonium salt obtained above was deprotected with trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 221.9 mg of the title compound (39.5% yield).

¹ H ЯМР (400 МГц, D ₂ O): δ 0,01 (м, 2H), 0,37-0,42 (м, 2H), 0,66-0,70 (м, 1H), 1,18-1,22 (м, 2H), 1,31-1,41 (м, 1H), 1,42-1,52 (дд, J=13,2 Гц, 1H), 1,73-2,06 (м, 5H), 2,15-2,20 (м, 1H), 2,32-2,35 (м, 1H), 3,01-3,05 (тд, J=2,8, 13,2 Гц, 1H), 3,13-3,16 (д, J=12,0 Гц, 1H), 3,30-3,33 (д, J=12,4 Гц, 1H), 3,46-3,49 (д, J=13,2 Гц, 1H), 3,98-4,02 (дд, 2,8, 12,8 Гц, 1H), 4,12-4,14 (д, 8,8 Гц, 1H), 4,18 (шир.с, 1H); MS m/z 446 [M+H] ⁺ .

Example 41

(2S,5R)-7-oxo-N'-{[(2S)-5-oxopyrrolidin-2-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

tert-Butyl (2S)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (S)-t-butyl 2-(hydrazine-carbonyl)-5-oxopyrrolidine-1-carboxylate (730 mg, prepared by the method of Reference Example 5 and Reference Example 6), to give 643.5 mg of the title compound (yield 9 0.9%).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,50 (с, 9H), 1,57-1,66 (м, 1H), 1,89-2,02 (м, 2H), 2,21-2,31 (м, 3H), 2,42-2,49 (м, 1H), 2,72-2,81 (м, 1H), 3,06 (м, 2H), 3,29 (шир.с, 1H), 4,01-4,02 (д, J=6,8 Гц, 1H), 4,59-4,62 (м, 1H), 4,87-4,90 (д, J=11,6 Гц, 1H), 5,02-5,05 (д, J=11,2 Гц, 1H), 7,34-7,41 (м, 5H), 8,25 (шир.с, 1H), 8,52 (шир.с, 1H); MS m/z 502 [M+H] ⁺ .

Stage 2

tert-Butyl (2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,45 (с, 9H), 1,76 (м, 1H), 1,88-1,99 (м, 1H), 2,05-2,19 (м, 2H), 2,22-2,26 (м, 1H), 2,34-2,50 (м, 2H), 2,58-2,68 (м, 1H), 3,12-3,16 (шир.д, J=12,4 Гц, 1H), 3,20-3,37 (д, J=12,0 Гц, 1H), 3,70 (шир.с, 1H), 3,94-3,96 (д, J=7,6 Гц, 1H), 4,66-4,69 (д, J=9,2 Гц, 1H); MS m/z 412 [M+H] ⁺ .

Stage 3

(2S,5R)-7-oxo-N'-{[(2S)-5-oxopyrrolidin-2-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Following the procedure of Example 17, from the total amount of the compound from step 2, tert-butyl (2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate tetrabutylammonium (quantitative yield) is obtained. Then, the total tetrabutylammonium salt was deprotected with trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 292.6 mg of the title compound (55.9% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.63-1.70 (m, 1H), 1.76-1.86 (m, 1H), 1.92-2.10 (m, 3H), 2.23-2.49 (m, 3H), 3.06-3.09 (d, J=12.0 Hz, 1H), 3.19-3.22 (d, J=12.0 Hz, 1H), 4.02-4.04 (d, J=11.2 Hz, 1H), 4.07 (br s, 1H), 4.27-4.30 (dd, J=5.2, 8.8 Hz, 1H); MS m/z 392 [M-Na+2H] ⁺ .

Example 42

(2S,5R)-7-oxo-N'-{[(2R)-5-oxopyrrolidin-2-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

tert-Butyl (2R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (R)-t-butyl 2-(hydrazine-carbonyl)-5-oxopyrrolidine-1-carboxylate (730 mg, prepared by the method of Reference Example 6 and Reference Example 4), to give 431.2 mg of the title compound (yield 6 0.9%).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,44 (с, 9H), 1,56 (м, 1H), 1,81-1,91 (м, 2H), 2,14-2,28 (м, 3H), 2,34-2,44 (м, 1H), 2,64-2,73 (м, 1H), 3,00-3,17 (м, 2H), 3,20 (с, 1H), 3,92-3,94 (д, J=7,2 Гц, 1H), 4,51-4,53 (д, J=5,6 Гц, 1H), 4,82-4,85 (д, J=11,2 Гц, 1H), 4,96-4,99 (д, J=11,6 Гц, 1H), 7,29-7,36 (м, 5H), 8,13 (шир.с, 1H), 8,43 (шир.с, 1H); MS m/z 502 [M+H] ⁺ .

Stage 2

tert-Butyl (2R)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative). MS m/z 412 [M+H] ⁺ .

Stage 3

(2S,5R)-7-oxo-N'-{[(2R)-5-oxopyrrolidin-2-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Using the procedure of Example 17, from the total amount of the compound from step 2, tert-butyl (2R)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate tetrabutylammonium (quantitative yield) is obtained. MS m/z 490 [M-Bu ₄ N] ^- .

The total amount of the tetrabutylammonium salt obtained above was deprotected with trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 179.5 mg of the title compound (50.5% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.67-1.71 (m, 1H), 1.78-1.86 (m, 1H), 1.92-2.16 (m, 3H), 2.26-2.45 (m, 3H), 3.04-3.07 (d, J=12.4 Hz, 1H), 3.19-3.22 (brd, J=12.0 Hz, 1H), 4.01-4.03 (d, J=8.4 Hz, 1H), 4.06 (br s, 1H), 4.22-4.28 (dd, J=4.8, 8.8 Hz, 1H); MS m/z 392 [M-Na+2H] ⁺ .

Example 43

(2S,5R)-N'-(furan-2-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

(2S,5R)-6-benzyloxy-N'-(furan-2-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 27, from the carboxylic acid (6b, 552 mg, 2.00 mmol) from Example 9 or 16 and furan-2-carboxamide (390 mg, prepared by the method of Reference Example 6 from the compound described in Reference Example 3) to give 291.8 mg of the title compound (37.9% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,57-1,65 (м, 1H), 1,89-2,02 (м, 2H), 2,33-2,38 (м, 1H), 3,10-3,13 (д, J=11,6 Гц, 1H), 3,21-3,24 (д, J=12,0 Гц, 1H), 3,31 (с, 1H), 4,07-4,12 (м, 1H), 4,89-4,92 (д, J=11,2 Гц, 1H), 5,03-5,06 (д, J=11,2 Гц, 1H), 6,50-6,52 (дд, J=1,6, 3,2 Гц, 1H), 7,17 (д, J=3,2 Гц, 1H), 7,32-7,43 (м, 5H), 7,47 (д, J=1,6 Гц, 1H), 8,41 (м, 1H), 8,62 (м, 1H); MS m/z 385 [M+H] ⁺ .

Stage 2

(2S,5R)-N'-(Furan-2-ylcarbonyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative). MS m/z 295 [M+H] ⁺ .

Stage 3

(2S,5R)-N'-(furan-2-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Following the procedure of Example 22, pyridinium (2S,5R)-N'-(furan-2-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide pyridinium was obtained from the total amount of the compound from step 2 and neutralized with saturated aqueous sodium bicarbonate and then purified by chromatography on a column of octadecyl silica gel with yielding 54.8 mg of the title compound (18.2% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.66-1.74 (m, 1H), 1.80-1.97 (m, 2H), 2.08-2.17 (m, 1H), 3.11-3.14 (d, J=12.0 Hz, 1H), 3.23-3.26 (d, J=12.4 Hz, 1H), 4 .09 (m, 2H), 6.51 (d, J=3.6 Hz, 1H), 7.13 (d, J=3.6 Hz, 1H), 7.58 (s, 1H); MS m/z 375 [M-Na+2H] ⁺ .

Example 44

(2S,5R)-N'-(1,3-oxazol-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N'-(1,3-oxazol-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Using the same procedure as in Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and oxazole-4-carbohydrazide (613 mg, prepared as in Reference Example 2), 335.2 mg of the title compound was obtained (61.7% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,63-1,65 (м, 1H), 1,80-2,00 (м, 2H), 2,29-2,37 (м, 1H), 3,08-3,11 (шир.д, J=13,2 Гц, 1H), 3,15-3,18 (д, J=1 2,0 Гц, 1H), 3,30 (шир.с, 1H), 4,07-4,08 (д, J=7,2 Гц, 1H), 4,87-4,91 (д, J=11,2 Гц, 1H), 5,02-5,06 (д, J=11,2 Гц, 1H), 7,34-7,42 (м, 5H), 7,88 (с, 1H), 8,25 (с, 1H), 8,61 (шир.с, 1H), 8,73 (шир.с, 1H); MS m/z 386 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-N'-(1,3-oxazol-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative). MS m/z 296 [M+H] ⁺ .

Stage 3

(2S,5R)-N'-(1,3-oxazol-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Following the procedure of Example 22, (2S,5R)-N'-(1,3-oxazol-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide pyridinium was obtained from the total amount of the compound from step 2 and neutralized with saturated aqueous sodium bicarbonate and then purified by chromatography on a column of octadecyl silica gel to give 195 mg of the title compound (56.5% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.70-1.73 (m, 1H), 1.75-1.88 (m, 1H), 1.93-1.97 (m, 1H), 2.06-2.14 (m, 1H), 3.09-3.12 (d, J=12.0 Hz, 1H), 3.18-3.24 (bd, J=12.8 Hz, 1H), 4.04-4.06 (d, J=7.6 Hz, 1H), 4.08-4.09 (m, 1H), 8.05 (s, 1H), 8.27 (s, 1H); MS m/z 376 [M-Na+2H] ⁺ .

Example 45

(2S,5R)-7-oxo-N'-(pyridin-3-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

(2S,5R)-6-Benzyloxy-7-oxo-N'-(pyridin-3-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

A solution of carboxylic acid (6b, 390 mg, 1.41 mmol) from example 9 or 16 in dry methylene chloride (14.1 ml) is cooled to 0°C under argon and isobutyl chloroformate (231.1 mg) is gradually added so that the temperature does not exceed 0°C. Next, triethylamine (185 mg) was gradually added so that the temperature did not exceed 0°C, the mixture was stirred for 30 minutes to obtain a mixed acid anhydride in the reaction system. To this reaction mixture was gradually added nicotinic acid hydrazide (580 mg). After the addition, the temperature was raised to room temperature and stirred for 1 hour. This reaction mixture was washed with 0.5M hydrochloric acid and brine, and the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-0/1, ethyl acetate/methanol=30/1) to obtain 439.5 mg of the title compound as a colorless oil (78.8% yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,68-1,75 (м, 1H), 1,88-2,02 (м, 2H), 2,25-2,30 (м, 1H), 3,08-3,11 (д, J=12,4 Гц, 1H), 3,28-3,33 (м, 1H), 3,60 (шир.с, 1H), 4,03-4,08 (д, J=12,0 Гц, 1H), 4,90 (д, J=11,2 Гц, 1H), 5,00 (д, J=11,2 Гц, 1H), 7,33-7,41 (м, 3H), 7,45-7,48 (м, 2H), 7,54-7,58 (дд, J=5,0, 8,0 Гц, 1H), 8,26-8,29 (дд, J=2,0, 8,0 Гц, 1H), 8,71-8,72 (дд, J=1,2, 4,8 Гц, 1H), 9,00-9,01 (дд, J=0,8, 2,0 Гц, 1H); MS m/z 396 [M+H] ⁺ .

Stage 2

(2S,5R)-6-hydroxy-7-oxo-N'-(pyridin-3-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

The total amount of the compound from step 1 above was dissolved in methanol (11 ml) and 10% palladium-carbon (water content 50%, 80 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. The catalyst from the reaction mixture was filtered through Celite, and the solvent was concentrated under reduced pressure to give 319.7 mg of the title compound (94.3% yield). MS m/z 306 [M+H] ⁺ .

Stage 3

(2S,5R)-7-oxo-N'-(pyridin-3-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

To a solution of the total compound from step 2 in pyridine (10.0 ml) was added sulfur trioxide-pyridine complex (796 mg) and the mixture was stirred at room temperature overnight. Methylene chloride was added to the reaction mixture, followed by filtration and concentration under reduced pressure. Toluene is added to the resulting residue, followed by azeotropic distillation. Pyridinium (2S,5R)-7-oxo-N'-(pyridin-3-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide is obtained and neutralized with saturated aqueous sodium bicarbonate, then purified by octadecyl silica gel column chromatography to give 193.1 mg of the title compounds (45.6% yield).

¹ H ЯМР (400 МГц, D ₂ O): δ 1,67-1,75 (м, 1H), 1,80-1,90 (м, 1H), 1,95-1,99 (м, 1H), 2,06-2,16 (м, 1H), 3,14-3,18 (д, J=12,4 Гц, 1H), 3,25-3,28 (шир.д, J=12,0 Гц, 1H), 4,10 (м, 2H), 7,46-7,49 (дд, J=5,2, 8,0 Гц, 1H), 8,12-8,14 (д, J=8,0 Гц, 1H), 8,58-8,60 (д, J=5,2 Гц, 1H), 8,81 (с, 1H); MS m/z 386 [M-Na+2H] ⁺ .

Example 46

(2S,5R)-7-oxo-N'-(pyridin-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

(2S,5R)-6-Benzyloxy-7-oxo-N'-(pyridin-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and isonicotinic acid hydrazide (580.1 mg, commercially available), the title compound was obtained (quantitative yield).

¹ H NMR (500 MHz, CDCl ₃ ): δ 1.60 (m, 1H), 1.97-2.04 (m, 2H), 2.34-2.36 (m, 1H), 3.15 (m, 2H), 3.35 (br s, 1H), 4.08-4.12 (m, 1H), 4.92-4.94 (d, J=11.0 Hz, 1H), 5.06-5.08 (d, J=11.0 Hz, 1H), 7.26-7.46 (m, 5H), 7.67-7.68 (m, 2H), 8.78-8.79 (m, 2H); MS m/z 396 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-7-oxo-N'-(pyridin-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.69-1.77 (m, 1H), 1.86-1.97 (m, 1H), 2.02-2.11 (m, 1H), 2.19-2.31 (m, 1H), 3.16-3.36 (m, 2H), 3.68 (br s, 1H), 3, 97-3.99 (d, J=6.8 Hz, 1H), 7.79-7.80 (d, J=6.0 Hz, 2H), 8.65-8.65 (d, J=6.4 Hz, 2H); MS m/z 306 [M+H] ⁺ .

Stage 3

(2S,5R)-7-oxo-N'-(pyridin-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Following the procedure of Example 26, (2S,5R)-7-oxo-N'-(pyridin-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide was obtained from the total amount of the compound from the above step 2 and neutralized with saturated aqueous sodium bicarbonate, then purified by octadecyl silica gel column chromatography to obtain 255.9 mg of the title compound (44.5% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.65-1.73 (m, 1H), 1.78-1.86 (m, 1H), 1.93-197 (m, 1H), 2.04-2.14 (m, 1H), 3.12-3.15 (d, J=12.0 Hz, 1H), 3.23-3.26 ( d, J=6.8 Hz, 1H), 4.08-4.10 (m, 2H), 7.72-7.73 (d, J=4.4 Hz, 2H), 8.60-8.61 (d, J=5.2 Hz, 2H); MS m/z 386 [M-Na+2H] ⁺ .

Example 47

N,N-dimethyl-2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide sodium

Stage 1

2-{[(2S,5R)-6-Benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-dimethylhydrazinecarboxamide

Following the procedure of Example 45, from the carboxylic acid (6b, 400 mg, 1.41 mmol) from Example 9 or 16 and N,N-dimethylhydrazinecarboxamide (491 mg, prepared by the method of Reference Example 3 and Reference Example 6), 385.2 mg of the title compound was obtained (73.6% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,61 (м, 1H), 1,90-2,02 (м, 2H), 2,32-2,37 (м, 1H), 2,95 (с, 6H), 3,05-3,08 (д, J=12,8 Гц, 1H), 3,25 (шир.с, 1H), 3,29-3,32 (д, J=12,0 Гц, 1H), 3,99-4,01 (д, J=6,8 Гц, 1H), 4,87-4,90 (д, J=11,2 Гц, 1H), 5,02-5,05 (д, J=11,2 Гц, 1H), 6,39 (шир.с, 1H), 7,34-7,41 (м, 5H), 8,24 (шир.с, 1H); MS m/z 361 [M+H] ⁺ .

Stage 2

2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-dimethylhydrazinecarboxamide

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative). MS m/z 272 [M+H] ⁺ .

Stage 3

N,N-dimethyl-2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide sodium

Following the procedure of Example 22, pyridinium 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-dimethylhydrazinecarboxamide pyridinium was obtained from the total amount of the compound from step 2 and neutralized with saturated aqueous sodium bicarbonate and then purified by chromatography on an octadecyl column. silica gel to give 305.2 mg of the title compound (77.1% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.64-1.72 (m, 1H), 1.76-1.87 (m, 1H), 1.93-1.98 (m, 1H), 2.07-2.12 (m, 1H), 2.81 (s, 6H), 3.11-3.14 (d, J=12.4 Hz, 1 H), 3.20-3.23 (d, J=12.4 Hz, 1H), 4.01-4.03 (d, J=11.2 Hz, 1H), 4.08-4.09 (m, 1H); MS m/z 352 [M-Na+2H] ⁺ .

Example 48

N,N-diethyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide sodium

Stage 1

2-{[(2S,5R)-6-Benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-diethylhydrazinecarboxamide

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and N,N-diethylhydrazinecarboxamide (656 mg, prepared by the method of Reference Example 3 and Reference Example 6), 108.6 mg of the title compound was obtained (19.7% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,16-1,19 (т, J=7,2 Гц, 6H), 1,55-1,62 (м, 1H), 1,89-2,05 (м, 2H), 2,24-2,36 (м, 1H), 3,06-3,09 (шир.д, J=12,4 Гц, 1H), 3,18-3,38 (м, 6H), 4,00-4,02 (шир.д, J=7,6 Гц, 1H), 4,87-4,90 (д, J=11,2 Гц, 1H), 5,04-5,06 (д, J=11,2 Гц, 1H), 6,36 (шир.с, 1H), 7,24-7,40 (м, 5H), 8,32 (шир.с, 1H); MS m/z 390 [M+H] ⁺ .

Stage 2

N,N-Diethyl 2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative). MS m/z 300 [M+H] ⁺ .

Stage 3

N,N-diethyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide sodium

Following the procedure of Example 22, pyridinium N,N-diethyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide pyridinium was obtained from the total amount of the compound from step 2 and neutralized with saturated aqueous sodium bicarbonate and then purified by chromatography on a column of octadecylsil icagel to give 63.0 mg of the title compound (56.4% yield).

¹ H NMR (400 MHz, D ₂ O): δ 0.97-1.01 (t, J=7.2 Hz, 6H), 1.62-1.68 (m, 1H), 1.70-1.85 (m, 1H), 1.92-1.96 (m, 1H), 2.05-2.11 (m, 1H), 3.09-3.22 ( m, 6H), 3.99-4.01 (d, J=7.8 Hz, 1H), 4.06 (br s, 1H); MS m/z 380 [M-Na+2H] ⁺ .

Example 49

2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide sodium

Stage 1

2-{[(2SR,5RS)-6-Benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide

Following the procedure of Example 30, from (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (100 mg, 0.36 mmol) and N-phenylhydrazinecarboxamide (60 mg) 134 mg of the title compound was obtained (94% yield). MS m/z 410 [M+H] ⁺ .

Stage 2

{[2SR,5RS)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide

Following the procedure of Example 17, 35 mg of the title compound was obtained from the total amount of the compound from Step 1 (yield 33%).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.76-1.82 (m, H), 1.91-1.98 (m, H), 2.04-2.08 (m, 1H), 2.25-2.31 (m, 1H), 3.17 (d, J=3.0, 1H), 3.25 (d, J=3.0, 1H), 3 .70 (br s, 1H), 4.00 (d, J=1.8, 1H), 7.00 (dd, J=2.1, 2.2, 1H), 7.23-7.28 (m, 1H), 7.39-7.42 (m, 1H); m/z 320 [M+H] ⁺ .

Stage 3

2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide sodium

Following the procedure of Example 30, pyridinium 2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide was prepared from the compound (30 mg, 0.10 mmol) from Step 2 above, neutralized with saturated aqueous sodium bicarbonate, and then purified by chromatography. on an octadecyl silica gel column to give 19 mg of the title compound (43% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.65-1.73 (m, 1H), 1.78-1.88 (m, 1H), 1.93-1.97 (m, 1H), 2.06-2.12 (m, 1H), 3.08 (d, J=3.0, 1H), 3.22 (d, J=3.2, 1H ), 4.06 (m, 2H), 7.18-7.27 (m, 5H); MS m/z 400 [M-Na+2H] ⁺ .

Example 50

(2S,5R)-N'-(morpholin-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N'-(morpholin-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and morpholine-4-carbohydrazide (584.3 mg, prepared by the method of Reference Example 3 and Reference Example 6), 323 mg of the title compound was obtained (56.8% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,58-1,65 (м, 1H), 1,91-2,02 (м, 2H), 2,32-2,37 (м, 1H), 3,06-3,09 (д, J=11,6 Гц, 1H), 3,24-3,27 (м, 1H), 3,36-3,46 (м, 4H), 3,63-3,69 (м, 4H), 4,00-4,02 (шир.д, J=7,6 Гц, 1H), 4,88-4,90 (д, J=11,2 Гц, 1H), 5,02-5,05 (д, J=11,2 Гц, 1H), 6,52 (шир.с, 1H), 7,34-7,42 (м, 5H), 8,30 (шир.с, 1H); MS m/z 404 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-N'-(morpholin-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative). MS m/z 314 [M+H] ⁺ .

Stage 3

(2S,5R)-N'-(morpholin-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Following the procedure of Example 22, pyridinium (2S,5R)-N'-(morpholin-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrozide pyridinium was obtained from the total amount of the compound from step 2 and neutralized with saturated aqueous sodium bicarbonate and then purified by chromatography on a column of octadecyl silica gel to give 152 mg of the title compound (45.7% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.65-1.72 (m, 1H), 1.78-1.88 (m, 1H), 1.94-1.98 (m, 1H), 2.07-2.13 (m, 1H), 3.10-3.13 (d, J=12.0 Hz, 1H), 3.21-3.24 (d, J=12.0 Hz, 1H), 3.32-3.35 (m, 4H), 3.61-3.63 (m, 4H), 4.02-4.04 (d, J=7.6 Hz, 1H), 4.08 (br s, 1H); MS m/z 394 [M-Na+2H] ⁺ .

Example 51

Methyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate sodium

Stage 1

Methyl {[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following the procedure of Example 17, from the carboxylic acid (6b, 1.30 g, 4.71 mmol) from Example 9 or 16 and methyl carbazate (538 mg), 1.64 g of the title compound was obtained (quantitative yield).

[α] _D ²⁰ +53.2° (c 0.60, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,56-1,68 (м, 1H), 1,90-2,08 (м, 2H), 2,30-2,40 (м, 1H), 3,02-3,20 (м, 2H), 3,30 (шир.с, 1H), 3,76 (шир.с, 3H), 4,01 (д, J=7,2 Гц, 1H), 4,91 (д, J=1 1,4 Гц, 1H), 5,06 (д, J=11,4 Гц, 1H), 6,59 (шир.с, 1H), 7,33-7,46 (м, 5H), 8,23 (шир.д, J=2,4 Гц, 1H); MS m/z 349 [M+H] ⁺ .

Stage 2

Methyl 2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following the procedure of Example 17, from the compound (2.11 g, 6.06 mmol) of Step 1 above, 1.22 g of the title compound was obtained (78% yield).

[α] _D ²⁰ -34.8° (c 0.57, MeOH); ¹ H NMR (400 MHz, CD ₃ OD): δ 1.70-1.79 (m, 1H), 1.87-1.98 (m, 1H), 2.02-2.12 (m, 1H), 2.26 (br.dd, J=14.6, 6.6 Hz, 1H), 3.12-3.25 (m, 2H), 3.67- 3.75 (m, 1H), 3.72 (s, 3H), 3.92 (brd, J=7.6 Hz, 1H); MS m/z 259 [M+H] ⁺ .

Stage 3

Methyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate sodium

To a solution of the compound (1.21 g, 4.70 mmol) from step 2 above in pyridine (30 ml) was added sulfur trioxide-pyridine complex (3.39 g) and the mixture was stirred at room temperature overnight. Methylene chloride was added to the reaction mixture, filtered, and then concentrated under reduced pressure. To the resulting residue was added toluene and subjected to azeotropic distillation and concentration to dryness. Saturated aqueous sodium dihydrogen phosphate (100 ml) was added, the aqueous layer was washed with ethyl acetate, tetrabutylammonium hydrogen sulfate (1.93 g) and ethyl acetate (10 ml) were added and stirred for 10 minutes. The aqueous layer is extracted with ethyl acetate. Then, the resulting organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride/acetone/triethylamine=49/49/2) to obtain 2.09 g of tetrabutylammonium methyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazidecarboxylate tetrabutylammonium.

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,01 (т, J=7,4 Гц, 12H), 1,45 (секст., J=7,4 Гц, 8H), 1,60-1,75 (м, 9H), 1,86-1,98 (м, 1H), 2,15-2,24 (м, 1H), 2,37 (шир.дд, J=15,0, 7,0 Гц, 1H), 3,05-3,20 (м, 1H), 3,25-3,34 (м, 8H), 3,38 (шир.д, J=11,6 Гц, 1H), 3,78 (с, 3H), 3,99 (д, J=7,6 Гц, 1H), 4,35 (шир.с, 1H), 6,55 (шир.с, 1H), 8,28 (шир.с, 1H); MS m/z 339 [M-Bu ₄ N+2H] ⁺ .

After treating the total tetrabutylammonium salt with DOWEX (Na type), the resulting crude product was purified to SP207 (acetonitrile/water=0/100-5/95) and lyophilized with 880 mg of the title compound (52% yield).

[a] _D ²¹ -37.6° (c 0.36, H ₂ O); ¹ H NMR (400 MHz, D ₂ O): δ 1.62-1.73 (m, 1H), 1.76-1.88 (m, 1H), 1.92-2.00 (m, 1H), 2.08 (brd, J=15.6, 6.8 Hz, 1H), 3.04 (brd, J=12.0 Hz, 1H), 3 .21 (brd, J=12.0 Hz, 1H), 3.61 (s, 3H), 4.02 (brd, J=7.6 Hz, 1H), 4.04-4.10 (m, 1H); MS m/z 339 [M-Na+2H] ⁺ ; Na content 7.9%.

Example 52

Ethyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate sodium

Stage 1

Ethyl 2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following the procedure of Example 17, from the carboxylic acid (6b, 352 mg, 1.27 mmol) from Example 9 or 16 and ethyl carbazate (184 mg), 388 mg of the title compound was obtained (84% yield).

[α] _D ²⁰ +53.4° (c 0.64, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,28 (т, J=7,2 Гц, 3H), 1,55-1,66 (м, 1H), 1,90-2,05 (м, 2H), 2,31-2,40 (м, 1H), 3,03-3,17 (м, 2H), 3,27-3,32 (м, 1H), 4,01 (д, J=7,2 Гц, 1H), 4,20 (кв., J=7,2 Гц, 2H), 4,92 (д, J=11,2 Гц, 1H), 5,06 (д, J=11,2 Гц, 1H), 6,47 (шир.с, 1H), 7,35-7,46 (м, 5H), 8,19 (шир.с, 1H); MS m/z 363 [M+H] ⁺ .

Stage 2

Ethyl 2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following the procedure of Example 17, from the compound (369 mg, 1.02 mmol) of Step 1 above, the title compound was obtained (quantitative yield).

[α] _D ²⁰ -29.9° (c 0.62, MeOH); ¹ H NMR (400 MHz, CD ₃ OD): δ 1.27 (brt, J=7.2 Hz, 3H), 1.68-1.82 (m, 1H), 1.87-1.99 (m, 1H), 2.01-2.15 (m, 1H), 2.27 (br dd, J=15.0, 6.6 Hz, 1H), 3 .11-3.25(m, 2H), 3.70(brs, 1H), 3.92(brd, J=7.2Hz, 1H), 4.16(sq, J=7.2Hz, 2H); MS m/z 273 [M+H] ⁺ .

Stage 3

Ethyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate sodium

Following the procedure of Example 22, pyridinium ethyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazidecarboxylate pyridinium was obtained from the total amount of the compound from step 2 and neutralized with saturated aqueous sodium bicarbonate, then purified by chromatography on a Diaion HP21 column (Mitsubishi Chemical) to give 108 mg of the title compound (2 steps, 29% yield).

[α] _D ²¹ -34.5° (c 0.52, H ₂ O); ¹ H ЯМР (400 МГц, D ₂ O): δ 1,11 (шир.т, J=7,2 Гц, 3H), 1,61-1,72 (м, 1H), 1,75-1,88 (м, 1H), 1,90-2,00 (м, 1H), 2,08 (шир.дд, J=15,2, 7,2 Гц, 1H), 3,03 (шир.д, J=12,0 Гц, 1H), 3,21 (шир.д, J=12,0 Гц, 1H), 4,05 (шир.д, J=7,6 Гц, 1H), 4,04 (кв., J=7,2 Гц, 2H), 4,07 (шир.с, 1H); MS m/z 353 [M-Na+2H] ⁺ .

Example 53

tert-Butyl 2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate sodium

Stage 1

tert-Butyl 2-{[(2SR,5RS)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following the procedure of Example 18, from (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (280 mg, 1.01 mmol) and t-butyl hydrazine carboxylate (147 mg) 299 mg of the title compound was obtained (68% yield).

¹H NMR (400 MHz, CDCl₃): δ 1.33 (s, 9H), 1.49-1.55 (m, 1H), 1.74-1.91 (m, 2H), 2.18-2.23 (m, 1H), 2.96 (m, 2H), 3.18 (br s, 1H), 3.78 (d, J=1.9, 1H), 4.78 (d, J= 2.8, 1H), 4.93 (d, J=2.8, 1H), 6.69 (s, 1H), 7.19-7.32 (m, 5H), 8.31 (s, 1H), MS m/z 391 [M+H]⁺.

Stage 2

tert-Butyl 2-{[(2SR,5RS)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following the procedure of Example 17, from (310 mg, 0.79 mmol) from Step 1 above, 200 mg of the title compound was obtained (84% yield). MS m/z 301 [M+H] ⁺ .

Stage 3

tert-Butyl 2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate sodium

Following the procedure of Example 18, pyridinium tert-butyl 2-{[(2SR, 5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate obtained from the compound (118 mg, 0.39 mmol) of the above step 2 was neutralized with saturated aqueous sodium bicarbonate and then purified octadecyl silica gel column chromatography to give 73 mg of the title compound (46% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.47 (s, 9H), 1.84-1.88 (m, 1H), 1.93-2.03 (m, 1H), 2.10-2.14 (m, 1H), 2.22-2.28 (m, 1H), 3.20 (d, J=3.0, 1H), 3.38 (d, J=3.1, 1H), 4.16 (d, J=1.7, 1H), 4.24 (br s, 1H); MS m/z 379 [M-Na] ^- .

Example 54

(2S,5R)-N'-(methylsulfonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N'-(methylsulfonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, from the carboxylic acid (6b, 345 mg, 1.25 mmol) from Example 9 or 16 and methanesulfonyl hydrazide (193 mg), 359 mg of the title compound was obtained (78% yield).

[α] _D ²⁰ +22.8° (c 0.55, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,54-1,66 (м, 1H), 1,96-2,09 (м, 2H), 2,26-2,36 (м, 1H), 2,74 (д, J=12,0 Гц, 1H), 3,02 (с, 3H), 3,11 (шир.д, J=12,0 Гц, 1H), 3,31-3,34 (м, 1H), 4,08 (д, J=7,6 Гц, 1H), 4,91 (д, J=11,4 Гц, 1H), 5,06 (д, J=11,4 Гц, 1H), 6,78 (шир.с, 1H), 7,35-7,48 (м, 5H), 8,71 (шир.с, 1H); MS m/z 369 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-N'-(methylsulfonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following the procedure of Example 17, from the compound (347 mg, 0.943 mmol) of Step 1 above, 259 mg of the title compound (yield quantitative) were obtained.

¹ H NMR (400 MHz, CD ₃ OD): δ 1.71-1.84 (m, 1H), 1.88-2.01 (m, 1H), 2.02-2.15 (m, 1H), 2.20-2.30 (m, 1H), 2.98-3.09 (m, 1H), 3.01 (s, 3H), 3.15 (brd, J=10.4 Hz, 1H), 3.67-3.75 (m, 1H), 3.93 (brd, J=7.6 Hz, 1H); MS m/z 279 [M+H] ⁺ .

Stage 3

(2S,5R)-N'-(methylsulfonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide sodium

Following the procedure of Example 22, from the compound (253 mg, 0.909 mmol) of the above step 2, (2S,5R)-N'-(methylsulfonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide pyridinium was obtained and neutralized with saturated aqueous sodium bicarbonate and then purified by column chromatography with octadecyl silica gel to give 65.9 mg of the title compound (19% yield).

[α] _D ²⁰ -44.1° (c 0.10, H ₂ O); ¹ H NMR (400 MHz, D ₂ O): δ 1.63-1.72 (m, 1H), 1.75-1.88 (m, 1H), 1.90-2.00 (m, 1H), 2.07 (brd, J=15.4, 7.0 Hz, 1H), 2.94 (d, J=12.0 Hz, 1H), 2.9 9 (s, 3H), 3.20 (bd, J=12.0 Hz, 1H), 4.01 (d, J=7.2 Hz, 1H), 4.03-4.09 (m, 1H); MS m/z 359 [M-Na+2H] ⁺ .

Example 55

(2SR,5RS)-N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2SR,5RS)-6-Benzyloxy-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (142 mg, 0.513 mmol) in methylene chloride (3.5 ml) was added triethylamine (226 μl), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg), 1- hydroxybenzotriazole (100 mg) and morpholine-4-amine (62.7 μl), then stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate) to obtain 149 mg of the title compound (80% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,57-1,66 (м, 1H), 1,86-2,06 (м, 2H), 2,37 (шир.дд, J=14,2, 6,8 Гц, 1H), 2,72 (д, J=11,8 Гц, 1H), 2,74-2,88 (м, 4H), 3,01 (шир.д, J=11,8 Гц, 1H), 3,28-3,33 (м, 1H), 3,81 (т, J=4,6 Гц, 4H), 3,90 (шир.д, J=7,6 Гц, 1H), 4,91 (д, J=11,4 Гц, 1H), 5,06 (д, J=11,4 Гц, 1H), 7,32-7,48 (м, 6H); MS m/z 361 [M+H] ⁺ .

Stage 2

(2SR,5RS)-6-hydroxy-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 17, from the compound (170 mg, 0.471 mmol) of Step 1 above, the title compound was obtained (yield quantitative).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,74-1,84 (м, 1H), 1,85-1,97 (м, 1H), 2,02-2,11 (м, 1H), 2,21 (шир.дд, J=14,8, 7,2 Гц, 1H), 2,81 (шир.т, J=4,4 Гц, 4H), 3,01 (д, J=11,6 Гц, 1H), 3,12 (шир.д, J=11,6 Гц, 1H), 3,69 (шир.с, 1H), 3,76 (шир.т, J=4,4 Гц, 4H), 3,81 (шир.д, J=7,6 Гц, 1H); MS m/z 271 [M+H] ⁺ .

Stage 3

(2SR,5RS)-N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Following the procedure of Example 22, pyridinium (2SR,5RS)-N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium was obtained from the total amount of the compound from step 2 and neutralized with saturated aqueous sodium bicarbonate, then purified by chromatography on a Sepabeads SP207 column (Mitsubish i Chemical) to give 104 mg of the title compound (2 steps, 63% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.65-1.85 (m, 2H), 1.90-1.99 (m, 1H), 2.00-2.08 (m, 1H), 2.68-2.80 (m, 4H), 3.97 (d, J=12.0 Hz, 1H), 3.18 (brd, J=12, 0 Hz, 1H), 3.70 (bt, J=4.6 Hz, 4H), 3.89 (b.d, J=7.0 Hz, 1H), 4.07 (b.d, J=5.6, 2.8 Hz, 1H); MS m/z 351 [M-Na+2H] ⁺ .

Example 56

(2S,5R)-N-Methoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N-methoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of the carboxylic acid (6b, 965 mg, 3.49 mmol) from Example 9 or 16 in tetrahydrofuran (20 ml) was added triethylamine (1.95 ml), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (802 mg), 1-hydroxybenzotriazole monohydrate (658 mg) and O-methylhydroxyamine hydrochloride (363 mg) and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/10) to obtain 773 mg of the title compound (72% yield).

[α] _D ²⁰ -19.8° (c 0.60, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,60-1,71 (м, 1H), 1,88-2,07 (м, 2H), 2,32 (шир.дд, J=14,2, 7,4 Гц, 1H), 2,80 (д, J=11,6 Гц, 1H), 3,00 (шир.д, J=11,6 Гц, 1H), 3,30-3,35 (м, 1H), 3,78 (с, 3H), 3,94 (д, J=7,6 Гц, 1H), 4,90 (д, J=11,6 Гц, 1H), 5,0 (д, J=11,6 Гц, 1H), 7,34-7,46 (м, 5H), 9,22 (шир.с, 1H); MS m/z 30 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-N-methoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 17, from the compound (770 mg, 2.52 mmol) of Step 1 above, 486 mg of the title compound was obtained (90% yield).

[α] _D ²⁰ -76.8° (c 0.34, MeOH); ¹ H NMR (400 MHz, CD ₃ OD): δ 1.74-1.84 (m, 1H), 1.86-1.98 (m, 1H), 2.03-2.13 (m, 1H), 2.20 (brd, J=15.0, 7.0 Hz, 1H), 3.05 (d, J=11.8 Hz, 1H), 3, 12 (brd, J=11.8 Hz, 1H), 3.66-3.74 (m, 1H), 3.71 (s, 3H), 3.82 (brd, J=7.6 Hz, 1H); MS m/z 216 [M+H] ⁺ .

Stage 3

(2S,5R)-N-Methoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Following the procedure of Example 17, from the compound (483 mg, 2.24 mmol) of Step 2 above, 963 mg of tetrabutylammonium (2S,5R)-N-methoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide was obtained.

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 0,93 (т, J=7,4 Гц, 12H), 1,37 (секст., J=7,4 Гц, 8H), 1,53-1,72 (м, 9H), 1,77-1,90 (м, 1H), 2,05-2,15 (м, 1H), 2,27 (шир.дд, J=14,8, 6,4 Гц, 1H), 2,84 (д, J=11,6 Гц, 1H), 3,14-3,31 (м, 9H), 3,73 (с, 3H), 3,87 (шир.д, J=7,6 Гц, 1H), 4,25 (шир.с, 1H), 9,32 (шир.с, 1H); MS m/z 296 [M-Na+2H] ⁺ .

The total tetrabutylammonium salt was ion exchanged with DOWEX (Na type) and then purified by octadecyl silica gel column chromatography to give 401 mg of the title compound (56% yield).

[α] _D ²⁰ -49.0° (c 0.85, H ₂ O); ¹ H NMR (400 MHz, D ₂ O): δ 1.66-1.87 (m, 2H), 1.91-2.07 (m, 2H), 3.02(d, J=12.0 Hz, 1H), 3.18 (brd, J=12.0 Hz, 1H), 3.62 (s, 3H), 3.92 (dd, J=8.0, 2.4 Hz, 1H), 4.07 (dd, J=6.0, 2.8 Hz, 1H); MS m/z 296 [M+H] ⁺ ; Na content 10.9%.

Example 57

(2SR,5RS)-N-Ethoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2SR,5RS)-6-Benzyloxy-N-ethoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Follow the procedure of Example 27 from (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (150 mg, 0.58 mmol) and O-ethylhydroxylamine hydrochloride (85 mg) to give 95 mg of the title compound (39% yield). MS m/z 320 [M+H] ⁺ .

Stage 2

(2SR,5RS)-N-Ethoxy-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 17, 88 mg of the title compound was obtained from the total amount of the compound from Step 1 (96% yield).

Stage 3

(2SR,5RS)-N-Ethoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Following the procedure of Example 18, pyridinium (2SR,5RS)-N-ethoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium was obtained from the total amount of the compound from step 2 and neutralized with aqueous sodium bicarbonate, then purified by octadecyl silica gel column chromatography to give 30 mg of the title compound ( yield 24%).

¹ H NMR (400 MHz, D ₂ O): δ 1.09 (t, J=1.7, 3H), 1.66-1.86 (m, 2H), 1.91-2.02 (m, 2H), 3.00 (d, J=3.0, 1H), 3.17 (d, J=2.9, 1H), 3.84 (square, J=1.7, 2H), 3.92 (d, J=1.7, 1H), 4.06 (m, 1H); MS m/z 308 [M-Na] ^- .

Example 58

(2S,5R)-N-(Cyclobutylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N-(cyclobutylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 45, from the carboxylic acid (6b, 379 mg, 1.37 mmol) from Example 9 or 16 and O-(cyclobutylmethyl)hydroxylamine (274 mg, prepared according to the procedure of Reference Example 7 and Reference Example 15), 359.4 mg of the title compound was obtained (73% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,55-2,15 (м, 9H), 2,28-2,39 (м, 1H), 2,59-2,72 (м, 1H), 2,77 (д, J=11,6 Гц, 1H), 3,00 (шир.д, J=11,6 Гц, 1H), 3,26-3,34 (м, 1H), 3,83-3,89 (м, 1H), 3,90-3,97 (м, 2H), 4,90 (д, J=11,4 Гц, 1H), 5,05 (д, J=11,4 Гц, 1H), 7,34-7,46 (м, 5H), 8,98 (с, 1H); MS m/z 360 [M+H] ⁺ .

Stage 2

(2S,5R)-N-(Cyclobutylmethoxy)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 17, the title compound was obtained from the total amount of the compound from Step 1 (yield quantitative). MS m/z 270 [M+H] ⁺ .

Stage 3

(2S,5R)-N-(Cyclobutylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Following the procedure of Example 18, pyridinium (2S,5R)-N-(cyclobutylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium was obtained from the total amount of the compound from step 2 and neutralized with saturated aqueous sodium bicarbonate, then purified by octadecyl silica gel column chromatography to obtain 157 .8 mg of the title compound (2 steps, 42% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.55-1.86 (m, 6H), 1.88-2.07 (m, 4H), 2.46-2.57 (m, 1H), 3.00 (d, J=12.0 Hz, 1H), 3.18 (brd, J=12.0 Hz, 1H), 3.79 (d, J= 7.2 Hz, 2H), 3.87-3.94 (m, 1H), 4.05-4.10 (m, 1H); MS m/z 350 [M-Na+2H] ⁺ .

Example 59

(2S,5R)-N-(2-Aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (II-059)

Stage 1

tert-Butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate

To a solution of the carboxylic acid (6b, 1.34 g, 4.87 mmol) from example 9 or 16 in methylene chloride (35 ml) was added triethylamine (2.71 ml), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g), 1-hydroxybenzotriazole monohydrate (1.15 g) and tert-butyl 2-(aminooxy)ethylcarb mat (1.12 g) described in Reference Example 9 was then stirred at room temperature overnight. Water was added to the residue obtained by concentrating the reaction solution under reduced pressure, followed by extraction with ethyl acetate. The resulting organic layer was washed with 0.1M hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/2-0/10) to obtain 1.77 g of the title compound (84% yield).

[α] _D ²⁰ -0.08° (c 0.29, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,44 (с, 9H), 1,56-1,70 (м, 1H), 1,90-2,09 (м, 2H), 2,25-2,38 (м, 1H), 2,76 (д, J=11,6 Гц, 1H), 3,03 (шир.д, J=11,6 Гц, 1H), 3,24-3,47 (м, 3H), 3,84-4,01 (м, 3H), 4,90 (д, J=11,6 Гц, 1H), 5,05 (д, J=11,6 Гц, 1H), 5,44 (шир.с, 1H), 7,34-7,48 (м, 5H), 9,37 (шир.с, 1H); MS m/z 435 [M+H]; 99.9% ee or more enantiomeric excess (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 ml/min; retention time 4.95 min (2R,5S), 6.70 min (2S,5R).

Stage 2

tert-Butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate

To a solution of the compound (3.91 g, 9.01 mmol) obtained in Step 1 above in methanol (80 ml) was added 10% palladium-carbon as a catalyst (water content 50%, 803 mg) and the mixture was stirred under hydrogen atmosphere for 45 minutes. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give 3.11 g of the title compound (quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.44 (s, 9H), 1.73-1.83 (m, 1H), 1.86-1.99 (m, 1H), 2.01-2.12 (m, 1H), 2.22 (br.dd, J=15.0, 7.0 Hz, 1H), 3.03 (d, J=1 2.0 Hz, 1H), 3.12 (brd, J=12.0 Hz, 1H), 3.25-3.35 (m, 2H), 3.68-3.71 (m, 1H), 3.82-3.91 (m, 3H); MS m/z 345 [M+H] ⁺ .

Stage 3

(2S,5R)-N-(2-Aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of the compound (3.09 g, 8.97 mmol) from Step 2 above in methylene chloride (80 ml) was added 2,6-lutidine (3.20 ml) and sulfur trioxide-pyridine complex (3.58 g) and the mixture was stirred at room temperature overnight. The reaction solution was poured into a half-saturated sodium bicarbonate aqueous solution, and the aqueous layer was washed with chloroform. Tetrabutylammonium hydrogen sulfate (3.47 g) and chloroform (30 ml) were added to the aqueous layer, and stirred for 10 minutes. The aqueous layer was extracted with chloroform, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5.46 g of tetrabutyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate tetrabutyl mmonium (yield 91%).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,01 (т, J=7,4 Гц, 12H), 1,37-1,54 (м, 8H), 1,45 (с, 9H), 1,57-1,80 (м, 9H), 1,85-1,98 (м, 1H), 2,14-2,24 (м, 1H), 2,30-2,39 (м, 1H), 2,83 (д, J=11,6 Гц, 1H), 3,20-3,50 (м, 11H), 3,85-3,99 (м, 3H), 4,33-4,38 (м, 1H), 5,51 (шир.с, 1H), 9,44 (шир.с, 1H); MS m/z 425 [M-Bu ₄ N+2H] ⁺ .

To a solution of tetrabutylammonium salt (5.20 g, 7.82 mmol) in methylene chloride (25 ml) was added trifluoroacetic acid (25 ml) under ice-cooling, and the mixture was stirred at 0° C. for 1 hour. The reaction solution is concentrated under reduced pressure. The resulting residue was washed with diethyl ether and adjusted to pH 7 with an aqueous sodium bicarbonate solution, and then purified by octadecyl silica gel (water) column chromatography, and then lyophilized to obtain 1.44 g of the title compound (57% yield).

[α] _D ²⁴ -63.5° (c 0.83, H ₂ O); ¹ H ЯМР (400 МГц, D ₂ O): δ 1,66-1,76 (м, 1H), 1,76-1,88 (м, 1H), 1,91-2,00 (м, 1H), 2,00-2,08 (м, 1H), 3,02(д, J=12,0 Гц, 1H), 3,15 (т, J=5,0 Гц, 2H), 3,18 (шир.д, J=12,0 Гц, 1H), 3,95 (дд, J=7,8, 2,2 Гц, 1H), 4,04 (т, J=5,0 Гц, 2H), 4,07 (дд, J=6,4, 3,2 Гц, 1H); MS m/z 325 [M+H] ⁺ .

Example 60

tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate sodium (II-060)

From the compound (1.700 g, 4.938 mmol) from Example 59 Step 2, tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}pyridinium carbamate was obtained and neutralized with saturated aqueous sodium bicarbonate, then purified octadecyl silica gel column chromatography to give 926.7 mg of the title compound (43.6% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.28 (s, 9H), 1.68-1.83 (m, 2H), 1.92-2.07 (m, 2H), 3.00-3.03 (d, J=12.8 Hz, 1H), 3.16-3.22 (m, 3H), 3.81-3.84 (d, J= 4.8 Hz, 2H), 3.90-3.92 (d, J=6.4 Hz, 1H), 4.06-4.07 (br s, 1H); MS m/z 423 [M-Na]-.

Example 61

(2S,5R)-N-[2-(Methylamino)ethoxy]7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (II-061)

Stage 1

tert-Butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and t-butyl (2-(aminooxy)ethyl)(methyl)carbamate (436 mg) described in Reference Example 16, 347.8 mg of the title compound was obtained (55% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,46 (с, 9H), 1,58-1,70 (м, 1H), 1,88-2,07 (м, 2H), 2,25-2,36 (м, 1H), 2,70-3,08 (м, 2H), 2,88 (с, 3H), 3,23-3,41 (м, 2H), 3,51-3,68 (м, 1H), 3,83-4,10 (м, 3H), 4,90 (д, J=11,4 Гц, 1H), 5,06 (д, J=11,4 Гц, 1H), 7,32-7,47 (м, 5H), 10,11 (шир.с, 1H); MS m/z 449 [M+H] ⁺ .

Stage 2

tert-Butyl {2-[({[(2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,46 (с, 9H), 1,73-1,83 (м, 1H), 1,86-2,00 (м, 1H), 2,01-2,13 (м, 1H), 2,14-2,28 (м, 1H), 2,93 (с, 3H), 3,04 (д, J=10,8 Гц, 1H), 3,08-3,18 (м, 1H), 3,43-3,55 (м, 2H), 3,65-3,72 (м, 1H), 3,79-3,88 (м, 1H), 3,92-4,05 (м, 2H); MS m/z 359 [M+H] ⁺ .

Stage 3

(2S,5R)-N-[2-(Methylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}tetrabutylammonium methylcarbamate (quantitative yield) was obtained.

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,01 (т, J=7,2 Гц, 12H), 1,36-1,53 (м, 8H), 1,47 (с, 9H), 1,57-1,77 (м, 9H), 1,83-1,98(м, 1H), 2,13-2,25 (м, 1H), 2,28-2,40 (м, 1H), 2,82-2,96 (м, 4H), 3,22-3,42 (м, 11H), 3,60-4,08 (м, 3H), 4,34 (шир.с, 1H), 10,15 (шир.с, 1H); MS m/z 437 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 149.4 mg of the title compound (3 steps, 57% yield).

¹ H NMR (500 MHz, D ₂ O): δ 1.73-1.97 (m, 2H), 1.98-2.07 (m, 1H), 2.08-2.18 (m, 1H), 2.74 (s, 3H), 3.09 (d, J=12.0 Hz, 1H), 3.21-3.32 (m, 3H), 4, 04 (dd, J=7.5, 2.0 Hz, 1H), 4.10-4.23 (m, 3H); MS m/z 337 [MH] ^- .

Example 62

(2S,5R)-N-[2-(Ethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}ethylcarbamate

Following the procedure of Example 27, from the carboxylic acid (6b, 414 mg, 1.50 mmol) from Example 9 or 16 and tert-butyl (2-(aminooxy)ethyl)(ethyl)carbamate (744 mg, prepared according to the procedure of Reference Example 7 and Reference Example 15), 541.6 mg of the title compound was obtained (78% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,11 (т, J=7,2 Гц, 3H), 1,46 (с, 9H), 1,58-1,74 (м, 1H), 1,89-2,08 (м, 2H), 2,24-2,38 (м, 1H), 2,72-2,91 (м, 1H), 2,92-3,11 (м, 1H), 3,12-3,42 (м, 4H), 3,43-3,66 (м, 1H), 3,85-4,05 (м, 3H), 4,90 (д, J=11,4 Гц, 1H), 5,06 (д, J=11,4 Гц, 1H), 7,33-7,47 (м, 5H), 10,18 (шир.с, 1H); MS m/z 463 [M+H] ⁺ .

Stage 2

tert-Butyl ethyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,22 (т, J=7,0 Гц, 3H), 1,46 (с, 9H), 1,73-1,84 (м, 1H), 1,86-1,98 (м, 1H), 2,02-2,12 (м, 1H), 2,14-2,27 (м, 1H), 3,04 (д, J=11,6 Гц, 1H), 3,09-3,18 (м, 1H), 3,25-3,37 (м, 2H), 3,43-3,54 (м, 2H), 3,66-3,72 (м, 1H), 3,79-3,88 (м, 1H), 3,89-4,03 (м, 2H); MS m/z 373 [M+H] ⁺ .

Stage 3

(2S,5R)-N-[2-(Ethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}ethylcarbamate tetrabutylammonium (quantitative yield) is obtained. MS m/z 451 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 166.6 mg of the title compound (3 steps, 40% yield).

¹ H NMR (500 MHz, D ₂ O): δ 1.25 (t, J=7.3 Hz, 3H), 1.73-1.83 (m, 1H), 1.84-1.95 (m, 1H), 1.97-2.15 (m, 2H), 3.05-3.13 (m, 3H), 3.22-3.29 (m, 3H ), 3.99-4.04 (m, 1H), 4.10-4.17 (m, 3H); MS m/z 353 [M+H] ⁺ .

Example 63

(2S,5R)-7-Oxo-N-[2-(propylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propylcarbamate

Following the procedure of Example 45, from the carboxylic acid (6b, 414 mg, 1.50 mmol) from Example 9 or 16 and tert-butyl (2-(aminooxy)ethyl)(propyl)carbamate (801 mg, prepared according to the procedure of Reference Example 7 and Reference Example 15), 552.2 mg of the title compound was obtained (77% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 0,87 (т, J=7,2 Гц, 3H), 1,45 (с, 9H), 1,53 (секст., J=7,2 Гц, 2H), 1,58-1,73 (м, 1H), 1,87-2,07 (м, 2H), 2,23-2,36 (м, 1H), 2,83 (д, J=11,2 Гц, 1H), 2,96-3,40 (м, 5H), 3,44-3,64 (м, 1H), 3,83-4,07 (м, 3H), 4,90 (д, J=11,4 Гц, 1H), 5,06 (д, J=11,4 Гц, 1H), 7,32-7,48 (м, 5H), 10,20 (шир.с, 1H); MS m/z 477 [M+H] ⁺

Stage 2

tert-Butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propylcarbamate

Following the procedure of Example 17, from the total amount of the compound from Step 1 above, 436.7 mg of the title compound was obtained (97% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ 0.89 (t, J=7.5 Hz, 3H), 1.40-1.61 (m, 2H), 1.46 (s, 9H), 1.66-2.00 (m, 2H), 2.02-2.28 (m, 2H), 3.04 (d, J=11.6 Hz, 1H), 3.09-3.19 (m, 1H), 3.24 (t, J=7.2 Hz, 2H), 3.42-3.56 (m, 2H), 3.62-3.74 (m, 1H), 3.79-4.05 (m, 3H); MS m/z 387 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[2-(propylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propyl tetrabutylammonium carbamate was obtained (quantitative yield). MS m/z 465 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 226.9 mg of the title compound (3 steps, 53% yield).

¹ H NMR (500 MHz, D ₂ O): δ 0.92 (t, J=7.5 Hz, 3H), 1.66 (sext., J=7.5 Hz, 2H), 1.74-1.82 (m, 1H), 1.83-1.94 (m, 1H), 1.97-2.13 (m, 2H), 3.00 (t, J=7, 5 Hz, 2H), 3.11 (d, J=12.0 Hz, 1H), 3.21-3.29 (m, 3H), 3.96-4.03 (m, 1H), 4.09-4.17 (m, 3H); MS m/z 367 [M+H] ⁺ .

Example 64

(2S,5R)-7-Oxo-N-[2-(propan-2-ylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (II-064)

Stage 1

tert-Butyl

Following the procedure of Example 45, from the carboxylic acid (6b, 414 mg, 1.50 mmol) from Example 9 or 16 and tert-butyl (2-(aminooxy)ethyl)(isopropyl)carbamate (596 mg) described in Reference Example 17, 578.4 mg of the title compound was obtained (81% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,15 (д, J=6,8 Гц, 6H), 1,46 (с, 9H), 1,55-1,70 (м, 1H), 1,89-2,07 (м, 2H), 2,25-2,37 (м, 1H), 2,73-2,90 (м, 1H), 2,98-3,08 (м, 1H), 3,22-3,38 (м, 2H), 3,40-3,60 (м, 1H), 3,83-4,06 (м, 4H), 4,90 (д, J=11,2 Гц, 1H), 5,06 (д, J=11,2 Гц, 1H), 7,35-7,46 (м, 5H), 10,29 (шир.с, 1H); MS m/z 477 [M+H] ⁺ .

Stage 2

tert-Butyl

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.09-1.23 (m, 6H), 1.46 (s, 9H), 1.73-2.27 (m, 4H), 3.06 (d, J=11.6 Hz, 1H), 3.08-3.50 (m, 4H), 3.64-3.73 (m, 1H), 3 .79-3.98 (m, 3H); MS m/z 387 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[2-(propan-2-ylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propan-2-ylcarbamate tetrabutylammonium was obtained (quantitative yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,01 (д, J=7,4 Гц, 12H), 1,10-1,20 (м, 6H), 1,33-1,77 (м, 17H), 1,46 (с, 9H), 1,84-1,97 (м, 1H), 2,12-2,25 (м, 1H), 2,28-2,40 (м, 1H), 2,79-2,95 (м, 1H), 3,17-3,45 (м, 9H), 3,50-3,67 (м, 1H), 3,80-4,07 (м, 5H), 4,34 (шир.с, 1H), 10,36 (шир.с, 1H); MS m/z 465 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 252.1 mg of the title compound (3 steps, 57% yield).

¹ H NMR (500 MHz, D ₂ O): δ 1.28 (d, J=6.5 Hz, 6H), 1.74-1.83 (m, 1H), 1.85-1.96 (m, 1H), 1.98-2.14 (m, 2H), 3.11 (d, J=12.5 Hz, 1H), 3.22-3.30 (m, 3H), 3.40 (quint, J=6.5 Hz, 1H), 4.01 (brd, J=5.5 Hz, 1H), 4.09-4.18 (m, 3H); MS m/z 367 [M+H] ⁺ .

Example 65

(2S,5R)-N-[2-(Dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

(2S,5R)-6-Benzyloxy-N-[2-(dimethylamino)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

A solution of carboxylic acid (6b, 553 mg, 2.00 mmol) from example 9 or 16 in anhydrous methylene chloride (10 ml) was cooled to 0° C. under argon, then isobutyl chloroformate (289 μl, 2.20 mmol) was added dropwise. Triethylamine (293 μl) is then added and stirred for 30 minutes. Then, a mixed acid anhydride is produced in the reaction system. 2-(Aminooxy)-N,N-dimethylethanamine dihydrochloride (591 mg) described in Referential Example 18 and triethylamine (930 µl) were gradually added to the reaction mixture while washing with anhydrous methylene chloride (7.0 ml), followed by stirring at the same temperature for 1 hour. The reaction mixture is filtered through Kiriyama filter paper. The residue is then washed with methanol, and the filtrate is concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride and water, and the organic layer was extracted with methylene chloride and dried over magnesium sulfate, then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (amino silica gel, chloroform/methanol=10/1) to obtain 291.1 mg of the title compound as a colorless oil (40% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.45-1.85 (m, 4H), 2.29 (s, 6H), 2.60 (t, J=5.2 Hz, 2H), 2.81 (d, J=11.6 Hz, 1H), 2.97 (brd, J=11.6 Hz, 1H), 3.28-3.34 (m , 1H), 3.92-4.07 (m, 3H), 4.90 (d, J=11.6 Hz, 1H), 5.05 (d, J=11.6 Hz, 1H), 7.35-7.48 (m, 5H); MS m/z 363 [M+H] ⁺ .

Stage 2

(2S,5R)-N-[2-(Dimethylamino)ethoxy]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,74-1,84 (м, 1H), 1,87-1,98 (м, 1H), 2,03-2,12 (м, 1H), 2,15-2,24 (м, 1H), 2,36 (с, 6H), 2,67-2,74 (м, 2H), 3,07 (шир.д, J=11,6 Гц, 1H), 3,12 (шир.д, J=11,6 Гц, 1H), 3,67-3,72 (м, 1H), 3,83 (шир.д, J=6,4 Гц, 1H), 3,96-4,06 (м, 2H); MS m/z 273 [M+H] ⁺ .

Stage 3

(2S,5R)-N-[2-(Dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 18, pyridinium (2S,5R)-N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium is obtained from the total amount of the compound from the above step 2 and neutralized with saturated aqueous sodium bicarbonate, then purified by chromatography on a column of octadecyl silicate lem to give 130.7 mg of the title compound (2 steps, 43% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.68-1.84 (m, 2H), 1.86-2.04 (m, 2H), 2.80 (s, 6H), 3.09-3.17 (m, 2H), 3.17-3.29 (m, 2H), 3.80-3.90 (m, 1H), 4.02- 4.13 (m, 3H); MS m/z 353 [M+H] ⁺ .

Example 66

(2S,5R)-N-{[(2S)-2-Aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (II-066)

Stage 1

tert-Butyl {(2S)-1-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-2-yl}carbamate

Following the procedure of Example 45, from the carboxylic acid (6b, 414 mg, 1.50 mmol) from Example 9 or 16 and (S)-tert-butyl (1-(aminooxy)propan-2-yl)carbamate (550 mg) described in Reference Example 19, 585.6 mg of the title compound was obtained (87% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,17 (д, J=6,4 Гц, 3H), 1,44 (с, 9H), 1,55-1,70 (м, 1H), 1,90-2,10 (м, 2H), 2,26-2,34 (м, 1H), 2,80 (д, J=12,0 Гц, 1H), 3,06 (шир.д, J=12,0 Гц, 1H), 3,27-3,34 (м, 1H), 3,64-3,74 (м, 1H), 3,86-3,98 (м, 3H), 4,81 (шир.д, J=7,6 Гц, 1H), 4,90 (д, J=11,6 Гц, 1H), 5,05 (д, J=11,6 Гц, 1H), 7,34-7,45 (м, 5H), 9,68 (шир.с, 1H); MS m/z 449 [M+H] ⁺ .

Stage 2

tert-Butyl {(2S)-1-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.16 (d, J=6.4 Hz, 3H), 1.44 (s, 9H), 1.74-1.84 (m, 1H), 1.86-1.98 (m, 1H), 2.03-2.12 (m, 1H), 2.21 (br.dd, J=15.2.6 .8 Hz, 1H), 3.06 (d, J=12.0 Hz, 1H), 3.14 (brd, J=12.0 Hz, 1H), 3.68-3.72 (m, 1H), 3.74-3.87 (m, 4H); MS m/z 359 [M+H] ⁺ .

Stage 3

(2S,5R)-N-{[(2S)-2-Aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl {(2S)-1-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate tetrabutylammonium is obtained (quantitative yield). MS m/z 437 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 117.1 mg of the title compound (3 steps, 26% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.17 (d, J=6.8 Hz, 3H), 1.66-1.89 (m, 2H), 1.91-2.08 (m, 2H), 3.02 (d, J=12.0 Hz, 1H), 3.18 (brd, J=12.0 Hz, 1H), 3.47-3, 58 (m, 1H), 3.82 (dd, J=11.8, 9.4 Hz, 1H), 3.92-4.02 (m, 2H), 4.05-4.10 (m, 1H); MS m/z 339 [M+H] ⁺ .

Example 67

(2S,5R)-N-{[(2R)-2-Aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (II-067)

Stage 1

tert-Butyl {(2R)-1-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate

Following the procedure of Example 45, from the carboxylic acid (6b, 414 mg, 1.50 mmol) from Example 9 or 16 and (R)-tert-butyl (1-(aminooxy)-2-yl)carbamate (569 mg, prepared according to the procedure of Reference Example 7 and Reference Example 15), 625 mg of the title compound was obtained (93% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,14 (д, J=6,4 Гц, 3H), 1,43 (с, 9H), 1,53-1,70 (м, 1H), 1,90-2,06 (м, 2H), 2,28-2,36 (м, 1H), 2,79 (д, J=12,0 Гц, 1H), 3,02 (шир.д, J=12,0 Гц, 1H), 3,28-3,33 (м, 1H), 3,56-3,68 (м, 1H), 3,84 (дд, J=11,2, 3,6 Гц, 1H), 3,92-4,04 (м, 2H), 4,66 (шир.д, J=8,0 Гц, 1H), 4,91 (д, J=11,2 Гц, 1H), 5,06 (д, J=11,2 Гц, 1H), 7,35-7,45 (м, 5H), 9,94 (шир.с, 1H); MS m/z 449 [M+H] ⁺ .

Stage 2

tert-Butyl {(2R)-1-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.15 (d, J=6.4 Hz, 3H), 1.44 (s, 9H), 1.73-1.84 (m, 1H), 1.86-2.00 (m, 1H), 2.01-2.12 (m, 1H), 2.19-2.29 (m, 1H), 3, 06 (d, J=11.6 Hz, 1H), 3.10-3.20 (m, 1H), 3.67-3.72 (m, 1H), 3.73-3.92 (m, 4H); MS m/z 359 [M+H] ⁺ .

Stage 3

(2S,5R)-N-{[(2R)-2-Aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl {(2R)-1-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate tetrabutylammonium is obtained (quantitative yield). MS m/z 437 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 212.6 mg of the title compound (3 steps, 45% yield).

¹ H ЯМР (400 МГц, D ₂ O): δ 1,17 (д, J=6,8 Гц, 3H), 1,66-1,78 (м, 1H), 1,78-1,88 (м, 1H), 1,90-2,06 (м, 2H), 3,02 (д, J=12,0 Гц, 1H), 3,18 (шир.д, J=12,0 Гц, 1H), 3,48-3,58 (м, 1H), 3,83 (дд, J=11,8, 9,0 Гц, 1H), 3,94 (шир.д, J=7,2 Гц, 1H), 3,98 (дд, J=11,8, 3,4 Гц, 1H), 4,06-4,10 (м, 1H); MS m/z 339 [M+H] ⁺ .

Example 68

(2S,5R)-N-{[(2S)-1-Aminopropan-2-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl {(2S)-2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate

Following the procedure of Example 45, from the carboxylic acid (6b, 414 mg, 1.50 mmol) from Example 9 or 16 and (S)-tert-butyl 2-(aminooxy)propyl)carbamate (597 mg, prepared according to the procedure of Reference Example 7 and Reference Example 15), 626.6 mg of the title compound was obtained (93% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,22 (д, J=6,4 Гц, 3H), 1,40-1,70 (м, 1H), 1,44 (с, 9H), 1,92-2,08 (м, 2H), 2,27-2,36 (м, 1H), 2,77 (д, J=11,6 Гц, 1H), 2,94-3,08 (м, 2H), 3,30-3,35 (м, 1H), 3,38-3,50 (м, 1H), 3,95-4,05 (м, 2H), 4,91 (д, J=11,4 Гц, 1H), 5,05 (д, J=11,4 Гц, 1H), 5,48-5,60 (м, 1H), 7,35-7,45 (м, 5H), 9,25 (шир.с, 1H); MS m/z 449 [M+H] ⁺ .

Stage 2

tert-Butyl {(2S)-2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,20 (д, J=6,4 Гц, 3H), 1,44 (с, 9H), 1,74-1,85 (м, 1H), 1,86-2,00 (м, 1H), 2,01-2,12 (м, 1H), 2,16-2,25 (м, 1H), 3,06 (д, J=11,6 Гц, 1H), 3,10-3,18 (м, 2H), 3,23-3,38 (м, 1H), 3,66-3,73 (м, 1H), 3,83-3,90 (м, 1H), 3,92-4,01 (м, 1H); MS m/z 359 [M+H] ⁺ .

Stage 3

(2S,5R)-N-{[(2S)-1-Aminopropan-2-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl {(2S)-2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}tetrabutylammonium carbamate is obtained (quantitative yield). MS m/z 437 [M-Bu ₄ N] ^- .

The total amount of the tetrabutylammonium salt obtained above was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 175.0 mg of the title compound (3 steps, 37% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.19 (d, J=6.4 Hz, 3H), 1.67-1.88 (m, 2H), 1.91-2.10 (m, 2H), 2.91-3.00 (m, 1H), 3.01-3.13 (m, 2H), 3.19 (brd, J=12.4 Hz, 1H), 3.95 (brd, J=7.2 Hz, 1H), 4.08 (br s, 1H), 4.11-4.20 (m, 1H); MS m/z 339 [M+H] ⁺ .

Example 69

(2S,5R)-N-(3-Aminopropoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (II-069)

Stage 1

tert-Butyl {3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and t-butyl (3-(aminooxy)propyl)carbamate (730 mg) described in Reference Example 20, 398.1 mg of the title compound was obtained (63% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,44 (с, 9H), 1,50-1,67 (м, 1H), 1,75-1,86 (м, 2H), 1,88-2,07 (м, 2H), 2,28-2,37 (м, 2H), 2,77 (д, J=11,0 Гц, 1H), 3,01 (шир.д, J=11,0 Гц, 1H), 3,20-3,38 (м, 3H), 3,89-4,04 (м, 3H), 4,90 (д, J=11,4 Гц, 1H), 5,05 (д, J=11,4 Гц, 1H), 5,17 (шир.с, 1H), 7,36-7,45 (м, 5H), 9,21 (шир.с, 1H); MS m/z 449 [M+H] ⁺ .

Stage 2

tert-Butyl {3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate

Following the procedure of Example 17, from the compound (392.8 mg, 876 μmol) of Step 1 above, the title compound was obtained (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.43 (s, 9H), 1.73-1.99 (m, 4H), 2.01-2.12 (m, 1H), 2.13-2.24 (m, 1H), 3.07 (d, J=11.6 Hz, 1H), 3.09-3.21 (m, 3H), 3 .69 (br s, 1H), 3.80-3.96 (m, 3H); MS m/z 359 [M+H] ⁺ .

Stage 3

(2S,5R)-N-(3-Aminopropoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl {3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}tetrabutylammonium carbamate is obtained (quantitative yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,01 (т, J=7,4 Гц, 12H), 1,33-1,53 (м, 8H), 1,47 (с, 9H), 1,55-1,96 (м, 12H), 2,14-2,23 (м, 1H), 2,31-2,41 (м, 1H), 2,85 (шир.д, J=11,2 Гц, 1H), 3,15-3,42 (м, 11H), 3,88-4,07 (м, 3H), 4,35 (шир.с, 1H), 5,27 (шир.с, 1H), 9,26 (шир.с, 1H); MS m/z 437 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 138.4 mg of the title compound (3 steps, 47% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.67-2.05 (m, 6H), 3.00-3.19 (m, 4H), 3.82-3.94 (m, 3H), 4.05-4.10 (m, 1H); MS m/z 337 [MH] ^- .

Example 70

(2S,5R)-2-(1,2-Oxazolidin-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one sodium

Stage 1

(2S,5R)-6-Benzyloxy-2-(1,2-oxazolidin-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octan-7-one

Following the procedure of Example 27, from the carboxylic acid (6b, 550 mg, 2.00 mmol) from Example 9 or 16 and 1,2-oxazolidine hydrochloride (328.6 mg, commercially available), 588 mg of the title compound was obtained (88.7% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.26-2.34 (m, 6H), 2.95 (m, 1H), 3.33 (m, 2H), 3.74 (m, 2H), 3.98-4.42 (m, 3H), 4.92 (m, 1H), 5.03-5.06 (m, 1H), 7, 26-7.52 (m, 5H); MS m/z 332 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-2-(1,2-oxazolidin-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octan-7-one

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative). MS m/z 242 [M+H] ⁺ .

Stage 3

(2S,5R)-2-(1,2-Oxazolidin-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one sodium

Following the procedure of Example 22, (2S,5R)-2-(1,2-oxazolidin-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one pyridinium was obtained from the total amount of the compound from the above step 2 and neutralized with saturated aqueous sodium bicarbonate, then purified by octadecyl silica gel column chromatography with yielding 281.3 mg of the title compound (46.9% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.79-1.98 (m, 4H), 2.28-2.30 (m, 2H), 3.13-3.24 (m, 2H), 3.61-4.33 (m, 6H); MS m/z 322 [M-Na+2H] ⁺ .

Example 71

(2S,5R)-2-(1,2-Oxazinan-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one sodium

Stage 1

(2S,5R)-6-Benzyloxy-2-(1,2-oxazinan-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octan-7-one

Following the procedure of Example 27, from the carboxylic acid (6b, 552 mg, 2.00 mmol) from Example 9 or 16 and 1,2-oxazinane (261 mg), 679 mg of the title compound was obtained (98.3% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.63-2.10 (m, 8H), 2.93-2.96 (brd, J=9.2 Hz, 1H), 3.28-3.31 (d, J=11.6 Hz, 1H), 3.34 (s, 1H), 3.61 (br s, 1H), 3.93-4, 14 (m, 3H), 4.47 (br s, 1H), 4.89-4.92 (d, J=11.2 Hz, 1H), 5.03-5.06 (d, J=11.6 Hz, 1H), 7.23-7.52 (m, 5H); MS m/z 346[M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-2-(1,2-oxazinan-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octan-7-one

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative). MS m/z 256 [M+H] ⁺ .

Stage 3

(2S,5R)-2-(1,2-Oxazinan-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one sodium

Following the procedure of Example 22, (2S,5R)-2-(1,2-oxazinan-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one pyridinium was obtained from the total amount of the compound from the above step 2, and neutralized with saturated aqueous sodium bicarbonate, then purified by octadecyl silica gel column chromatography to obtain m 297 mg of the title compound (42.4% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.64-1.97 (m, 8H), 2.99-3.16 (m, 1H), 3.21-3.24 (d, J=12.0 Hz, 1H), 3.54-4.37 (m, 6H); MS m/z 336 [M-Na+2H] ⁺ .

Example 72

(2S,5R)-N-[2-(Morpholin-4-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N-[2-(morpholin-4-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 45, from the carboxylic acid (6b, 414 mg, 1.50 mmol) from Example 9 or 16 and O-(2-morpholinoethyl)hydroxylamine (306 mg, Huhu Technology) 629.6 mg of the title compound was obtained (quantitative yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,60-1,73 (м, 1H), 1,85-2,06 (м, 2H), 2,33 (шир.дд, J=14,4, 7,6 Гц, 1H), 2,46-2,60 (м, 4H), 2,62-2,74 (м, 2H), 2,80 (д, J=11,8 Гц, 1H), 2,98 (шир.д, J=11,8 Гц, 1H), 3,28-3,34 (м, 1H), 3,70-3,81 (м, 4H), 3,93 (шир.д, J=7,2 Гц, 1H), 3,97-4,11 (м, 2H), 4,90 (д, J=11,2 Гц, 1H), 5,06 (д, J=11,2 Гц, 1H), 7,35-7,45 (м, 5H), 9,93 (шир.с, 1H); MS m/z 405 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-N-[2-(morpholin-4-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 17, from the total amount of the compound from Step 1 above, 452.4 mg of the title compound was obtained (96% yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,77-1,85 (м, 1H), 1,86-1,98 (м, 1H), 2,03-2,13 (м, 1H), 2,16-2,25 (м, 1H), 2,50-2,61 (м, 4H), 2,68 (т, J=5,4 Гц, 2H), 3,05 (д, J=11,6 Гц, 1H), 3,12 (шир.д, J=11,6 Гц, 1H), 3,67-3,74 (м, 5H), 3,84 (шир.д, J=7,2 Гц, 1H), 4,02-4,06 (м, 2H); MS m /z 315 [M+H] ⁺ .

Stage 3

(2S,5R)-N-[2-(Morpholin-4-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Following the procedure of Example 18, pyridinium (2S,5R)-N-[2-(morpholin-4-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium is obtained from the total amount of the compound from the above step 2 and neutralized with saturated aqueous sodium bicarbonate, then purified by chromatography on a column of octadecyl silica gel to give 30.9 mg of the title compound (4 steps, 21% yield).

¹ H NMR (500 MHz, D ₂ O): δ 1.77-1.87 (m, 2H), 1.93-2.06 (m, 2H), 2.51-2.65 (m, 4H), 2.67 (t, J=5.5 Hz, 2H), 3.16 (brd, J=11.8 Hz, 1H), 3.24 (d, J=1 1.8 Hz, 1H), 3.66-3.76 (m, 4H), 3.85 (brd, J=5.0 Hz, 1H), 3.95 (t, J=5.5 Hz, 2H), 4.13 (br s, 1H); MS m/z 395 [M-Na+2H] ⁺ .

Example 73

(2S,5R)-7-Oxo-N-[2-(piperazin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl 4-{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}piperazine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 552 mg, 2.00 mmol) from Example 9 or 16 and tert-butyl 4-(2-(aminooxy)ethyl)piperazine-1-carboxylate (735 mg, prepared according to the procedure of Reference Example 7 and Reference Example 15), 476.5 mg of the title compound was obtained (47.3% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,45 (с, 9H), 1,64-2,06 (м, 3H),2,30-2,35 (м, 1H), 2,58-2,66 (м, 4H), 2,68-2,69 (м, 2H), 2,77-2,80 (д, J=11,6 Гц, 1H), 2,96-2,99 (д, J=11,6 Гц, 1H), 3,31 (шир.с, 1H), 3,79-3,82 (м, 4H), 3,92-3,94 (д, J=8,0 Гц, 1H), 3,99-4,09 (м, 2H), 4,88-4,92 (д, J=11,2 Гц, 1H), 5,04-5,07 (д, J=11,6 Гц, 1H), 7,34-7,42 (м, 5H); MS m/z 504 [M+H] ⁺ .

Stage 2

tert-Butyl 4-{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}piperazine-1-carboxylate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative). MS m/z 414 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[2-(piperazin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl 4-{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}piperazine-1-carboxylate tetrabutylammonium is obtained (quantitative yield). MS m/z 492 [M-Bu ₄ N] ^- .

The total amount of the tetrabutylammonium salt obtained above was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 12.3 mg of the title compound (3.3% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.74 (m, 2H), 1.76 (m, 2H), 2.65-2.69 (m, 6H), 2.96 (m, 4H), 2.98-2.99 (d, J=5.2 Hz, 1H), 3.17-3.20 (d, J=10.8 Hz, 1H), 3.86-3.89 (m, 3H), 4.04 (br s, 1H); MS m/z 394 [M+H] ⁺ .

Example 74

(2S,5R)-7-Oxo-N-[2-(1,4-diazepan-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl 4-{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1,4-diazepine-1-carboxylate

Following the procedure of Example 17, from the carboxylic acid (6b, 548 mg, 1.98 mmol) from Example 9 or 16 and tert-butyl 4-(2-(aminooxy)ethyl)-1,4-diazepine-1-carboxylate (921 mg, prepared according to the procedure of Reference Example 7 and Reference Example 15), 1.13 g of the title compound was obtained. MS m/z 518 [M+H] ⁺ .

Stage 2

tert-Butyl 4-{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1,4-diazepine-1-carboxylate

Following the procedure of Example 17, from the total amount of the compound from the above Step 1, 910 mg of the title compound were obtained. MS m/z 428 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[2-(1,4-diazepan-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of the total compound from Step 2 above in methylene chloride (20 ml) was added 2,6-lutidine (692 μl) and sulfur trioxide-pyridine complex (945 mg) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to give 1.67 g of tert-butyl 4-{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1,4-diazepine-1-pyridinium carboxylate. MS m/z 506 [M-C ₅ H ₅ NH] ^- .

The pyridinium salt obtained above (1.00 g, 1.19 mmol) was dissolved in methylene chloride (2.0 ml), and trifluoroacetic acid (2.0 ml) was added under ice-cooling, and the mixture was stirred at 0° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether and adjusted to pH 7 with an aqueous sodium bicarbonate solution, then purified by octadecyl silica gel column chromatography to obtain (methanol/water=0/10-5/5). After lyophilization, 111 mg of the title compound are obtained (4 steps, 23% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.64-2.07 (m, 6H), 2.73-2.85 (m, 4H), 2.90-3.04 (m, 3H), 3.13-3.28 (m, 5H), 3.90-3.98 (m, 3H), 4.05-4.09 (m, 5H); MS m/z 408 [M+H] ⁺ .

Example 75

(2S,5R)-N-[(2S)-Azetidin-2-ylmethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (II-075)

Stage 1

tert-Butyl (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate

Following the procedure of Example 45, from the carboxylic acid (6b, 553 mg, 2.00 mmol) from Example 9 or 16 and (S)-tert-butyl 2-((aminooxy)methyl)azetidine-1-carboxylate (578 mg) described in Reference Example 21, 760.1 mg of the title compound was obtained (83% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,46 (с, 9H), 1,56-1,70 (м, 1H), 1,88-2,07 (м, 3H), 2,23-2,34 (м, 2H), 2,84 (д, J=11,6 Гц, 1H), 3,02 (д, J=11,6 Гц, 1H), 3,28 (шир.с, 1H), 3,77-4,03 (м, 4H), 4,06-4,15 (м, 1H), 4,37-4,48 (м, 1H), 4,89 (д, J=11,6 Гц, 1H), 5,04 (д, J=11,6 Гц, 1H), 7,34-7,44 (м, 5H), 10,63 (шир.с, 1H); MS m/z 461 [M+H] ⁺ .

Stage 2

tert-Butyl (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate

Following the procedure of Example 17, from the compound (699 mg, 1.52 mmol) of Step 1 above, the title compound was obtained (yield quantitative).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,44 (с, 9H), 1,74-1,85 (м, 1H), 1,86-1,99 (м, 1H), 2,02-2,14 (м, 1H), 2,16-2,40 (м, 3H), 3,06 (д, J=11,6 Гц, 1H), 3,10-3,17 (м, 1H), 3,67-3,74 (м, 1H), 3,75-3,93 (м, 3H), 4,01 (дд, J=10,6, 10,6 Гц, 1H), 4,14 (дд, J=10,6, 10,6 Гц, 1H), 4,37-4,47 (м, 1H); MS m/z 371 [M+H] ⁺ .

Stage 3

(2S,5R)-N-[(2S)-Azetidin-2-ylmethoxy]7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl (2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate tetrabutylammonium is obtained (quantitative yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.01 (t, J=7.2 Hz, 12H), 1.30-2.10 (m, 19H), 1.46 (s, 9H), 2.12-2.39 (m, 3H), 2.89 (brd, J=12.0 Hz, 1H), 3.23-3.39 (m, 9H), 3.76-3.93 (m, 3H), 3.95-4.06 (m, 1H), 4.08-4.18 (m, 1H), 4.33 (br s, 1H), 4.37-4.50 (m, 1H); MS m/z 449 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 172.3 mg of the title compound (3 steps, 32% yield).

¹ H NMR (500 MHz, D ₂ O): δ 1.71-1.83 (m, 1H), 1.84-1.97 (m, 1H), 1.98-2.16 (m, 2H), 2.36-2.49 (m, 1H), 2.50-2.61 (m, 1H), 3.10 (d, J=12.0 Hz, 1 H), 3.22-3.30 (m, 1H), 3.92-4.12 (m, 5H), 4.25-4.36 (m, 1H), 4.68-4.77 (m, 1H); MS m/z 351 [M+H] ⁺ .

Example 76

(2S,5R)-7-Ooxo-N-[(2S)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and (S)-tert-butyl 2-(aminooxy)methyl)pyrrolidine-1-carboxylate (649 mg, prepared according to the procedure of Reference Example 7 and Reference Example 13), 477 mg of the title compound was obtained (71% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,46 (с, 9H), 1,62-1,77 (м, 1H), 1,70-2,07 (м, 6H), 2,21-2,37 (м, 1H), 2,88 (шир.д, J=12,4 Гц, 1H), 2,98-3,10 (м, 1H), 3,25-3,38 (м, 3H), 3,65-4,05 (м, 3H), 4,08-4,24 (м, 1H), 4,90 (д, J=11,6 Гц, 1H), 5,05 (д, J=11,6 Гц, 1H), 7,32-7,46 (м, 5H), 10,22 (с, 1H); MS m/z 475 [M+H] ⁺ .

Stage 2

tert-Butyl (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.46 (s, 9H), 1.72-2.27 (m, 8H), 2.99-3.18 (m, 2H), 3.25-3.56 (m, 2H), 3.66-4.10 (m, 5H); MS m/z 385 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[(2S)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 26, from the total amount of the compound from the above step 2, 385.6 mg of tert-butyl (2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyridinium pyrrolidine-1-carboxylate (71%) is obtained.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.45 (s, 9H), 1.65-2.57 (m, 8H), 2.96-3.12 (m, 1H), 3.25-3.44 (m, 4H), 3.68-4.18 (m, 3H), 4.25 (br s, 1H), 7.92-8, 00 (m, 2H), 8.45 (dd, J=7.6, 7.6 Hz, 1H), 8.98-9.07 (m, 1H), 10.61 (br s, 1H); MS m/z 463 [MC ₅ H ₅ NH] ^- .

The total amount of the pyridinium salt obtained above was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 58.1 mg of the title compound (3 steps, 16% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.78-2.12 (m, 8H), 3.04 (d, J=12.4 Hz, 1H), 3.18 (brd, J=12.4 Hz, 1H), 3.24 (t, J=7.2 Hz, 2H), 3.83 (ddd, J=8.2, 8.2, 3.4 Hz, 1H), 3.89-3.97 (m, 2H), 4.04-4.11 (m, 2H); MS m/z 365 [M+H] ⁺ .

Example 77

(2S,5R)-7-Oxo-N-[(2R)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (II-077)

Stage 1

tert-Butyl (2R)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and (R)-tert-Butyl 2-((aminooxy)methyl)pyrrolidine-1-carboxylate (796 mg) described in Reference Example 22, 336 mg of the title compound was obtained (50% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,45 (с, 9H), 1,52-1,72 (м, 1H), 1,80-2,09 (м, 6H), 2,27-2,39 (м, 1H), 2,84 (шир.д, J=12,4 Гц, 1H), 2,96-3,08 (м, 1H), 3,28-3,44 (м, 3H), 3,60-3,86 (м, 2H), 3,89-4,06 (м, 1H), 4,14-4,29 (м, 1H), 4,90 (д, J=11,2 Гц, 1H), 5,06 (д, J=11,2 Гц, 1H), 7,32-7,47 (м, 5H), 10,56 (с, 1H); MS m/z 475 [M+H] ⁺ .

Stage 2

tert-Butyl (2R)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.46 (s, 9H), 1.73-2.27 (m, 8H), 3.06 (d, J=11.6 Hz, 1H), 3.09-3.18 (m, 1H), 3.24-3.40 (m, 2H), 3.67-3.71 (m, 1H), 3 .73-4.12 (m, 4H); MS m/z 385 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[(2R)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium pyrrolidine-1-carboxylate was obtained (quantitative yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,01 (т, J=7,4 Гц, 12H), 1,34-1,51 (м, 8H), 1,46 (с, 9H), 1,55-1,78 (м, 10H), 1,80-2,01 (м, 4H), 2,11-2,23 (м, 1H), 2,29-2,42 (м, 1H), 2,88 (шир.д, J=11,2 Гц, 1H), 3,21-3,43 (м, 10H), 3,60-3,86 (м, 2H), 3,88-4,07 (м, 2H), 4,16-4,28 (м, 1H), 4,34 (шир.с, 1H), 10,62 (шир.с, 1H); MS m/z 463 [M-Bu ₄ N+2H] ⁺ .

The total amount of the tetrabutylammonium salt obtained above was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 77.4 mg of the title compound (3 steps, 30% yield).

¹ H NMR (500 MHz, D ₂ O): δ 1.66-2.18 (m, 8H), 3.14 (d, J=12.8 Hz, 1H), 3.23 (brd, J=12.8 Hz, 1H), 3.30 (t, J=7.3 Hz, 2H), 3.89 (ddd, J=8.2, 8.2, 3.4 Hz, 1H), 3.92-4.01 (m, 2H), 4.09-4.18 (m, 2H); MS m/z 365 [M+H] ⁺ .

Example 78

(2S,5R)-7-Oxo-N-[(2S)-piperidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (II-078)

Stage 1

tert-Butyl (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate

Following the procedure of Example 45, from the carboxylic acid (6b, 553 mg, 2.00 mmol) from Example 9 or 16 and (S)-tert-Butyl 2-((aminooxy)methyl)piperidine-1-carboxylate (300 mg) described in Reference Example 23, 353.3 mg of the title compound was obtained (72% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,30-1,75 (м, 7H), 1,46 (с, 9H), 1,90-2,10 (м, 2H), 2,22-2,34 (м, 1H), 2,72-2,90 (м, 1H), 2,85 (д, J=11,2 Гц, 1H), 3,09 (шир.д, J=11,2 Гц, 1H), 3,26-3,32 (м, 1H), 3,68-3,84 (м, 1H), 3,90-4,01 (м, 2H), 4,06-4,15 (м, 1H), 4,44-4,58 (м, 1H), 4,90 (д, J=11,4 Гц, 1H), 5,05 (д, J=11,4 Гц, 1H), 7,35-7,46 (м, 5H), 10,14 (шир.с, 1H); MS m/z 489 [M+H] ⁺ .

Stage 2

tert-Butyl (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,33-1,70 (м, 5H), 1,45 (с, 9H), 1,74-2,00 (м, 3H), 2,03-2,12 (м, 1H), 2,17-2,26 (м, 1H), 2,82-2,93 (м, 1H), 3,06 (д, J=12,0 Гц, 1H), 3,14 (шир.д, J=12,0 Гц, 1H), 3,68-3,92 (м, 1H), 3,84 (шир.д, J=6,8 Гц, 1H), 3,92-4,08 (м, 3H), 4,43-4,51 (м, 1H); MS m/z 399 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[(2S)-piperidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl (2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate tetrabutylammonium is obtained (quantitative yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,01 (т, J=7,2 Гц, 12H), 1,14-1,79 (м, 23H), 1,45 (с, 9H), 1,84-2,00 (м, 1H), 2,12-2,23 (м, 1H), 2,24-2,38 (м, 1H), 2,72-2,83 (м, 1H), 2,92 (шир.д, J=12,8 Гц, 1H), 3,21-3,34 (м, 8H), 3,36-3,45 (м, 1H), 3,72-4,18 (м, 4H), 4,35 (шир.с, 1H), 4,45-4,56 (м, 1H); MS m/z 477 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 52.8 mg of the title compound (3 steps, 19% yield).

¹ H ЯМР (400 МГц, D ₂ O): δ 1,31-1,60 (м, 3H), 1,68-1,89 (м, 5H), 1,92-2,10 (м, 2H), 2,82-2,91 (м, 1H), 3,05 (д, J=12,0 Гц, 1H), 3,18 (шир.д, J=12,0 Гц, 1H), 3,26-3,40 (м, 2H), 3,87 (дд, J=11,8, 9,0 Гц, 1H), 3,94 (шир.д, J=7,2 Гц, 1H), 3,97 (дд, J=11,8, 3,4 Гц, 1H), 4,07-4,12 (м, 1H); MS m/z 377 [MH] ^- .

Example 79

(2S,5R)-N-(Azetidin-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl 3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and tert-butyl 3-(aminooxy)azetidine-1-carboxylate (375 mg, prepared according to the procedure of Reference Example 7 and Reference Example 13), 558 mg of the title compound was obtained (84% yield).

[α] _D ²⁴ -17.0° (c 0.30, CHCl ₃ ); ¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,43 (с, 9H), 1,57-1,70 (м, 1H), 1,84-2,07 (м, 2H), 2,31 (шир.дд, J=14,6, 7,4 Гц, 1H), 2,41 (д, J=11,4 Гц, 1H), 3,01 (шир.д, J=11,4 Гц, 1H), 3,29-3,34 (м, 1H), 3,93-4,03 (м, 2H), 4,05-4,16 (м, 2H), 4,69-4,76 (м, 1H), 4,90 (д, J=11,6 Гц, 1H), 5,05 (д, J=11,6 Гц, 1H), 7,33-7,45 (м, 5H), 8,18 (шир.с, 1H); MS m/z 447 [M+H] ⁺ .

Stage 2

tert-Butyl 3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate

Following the procedure of Example 17, from the compound (543 mg, 1.22 mmol) from the above Step 1, 428 mg of the title compound (99%) are obtained.

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,44 (с, 9H), 1,72-1,84 (м, 1H), 1,85-1,99 (м, 1H), 2,00-2,11 (м, 1H), 2,15-2,24 (м, 1H), 3,00 (д, J=11,6 Гц, 1H), 3,11 (шир.д, J=11,6 Гц, 1H), 3,69 (шир.с, 1H), 3,85 (шир.д, J=7,6 Гц, 1H), 3,88-4,00 (м, 2H), 4,03-4,17 (м, 2H), 4,67-4,76 (м, 1H); MS m/z 357 [M+H] ⁺ .

Stage 3

(2S,5R)-N-(Azetidin-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 59, from the total amount of the compound (424 mg, 1.19 mmol) from the above step 2, 739 mg of tert-butyl 3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate (yield 91%) is obtained.

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,01 (т, J=7,4 Гц, 12H), 1,37-1,53 (м, 8H), 1,44 (с, 9H), 1,57-1,78 (м, 9H), 1,83-1,96 (м, 1H), 2,14-2,23 (м, 1H), 2,34 (шир.дд, J=15,0, 7,0 Гц, 1H), 2,79 (д, J=11,6 Гц, 1H), 3,23-3,40 (м, 9H), 3,93 (шир.д, J=7,6 Гц, 1H), 3,95-4,15 (м, 4H), 4,33-4,38 (м, 1H), 4,70-4,78 (м, 1H), 9,24 (шир.с, 1H); MS m/z 435 [M-Bu ₄ N] ^- .

The tetrabutylammonium salt (720 mg, 1.06 mmol) was deprotected with trifluoroacetic acid and purified by octadecyl silica gel column chromatography to give 144 mg of the title compound (40% yield).

[α] _D ²⁵ -69.2° (c 0.32, H ₂ O); ¹ H NMR (400 MHz, D ₂ O): δ 1.67-1.78 (m, 1H), 1.78-1.89 (m, 1H), 1.92-2.09 (m, 2H), 3.00 (d, J=12.2 Hz, 1H), 3.20 (brd, J=12.2 Hz, 1H), 3.97 (brd, J=7.2 Hz, 1H), 4.04-4.14 (m, 3H), 4.25-4.33 (m, 2H), 4.76-4.84 (m, 1H); MS m/z 337 [M+H] ⁺ .

Example 80

(2S,5R)-7-Oxo-N-[(3R)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl (3R)-3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 553 mg, 2.00 mmol) from Example 9 or 16 and (R)-tert-butyl 3-(aminooxy)pyrrolidine-1-carboxylate (606 mg) described in Reference Example 13, 904.6 mg of the title compound was obtained (98.3% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,46 (с, 9H), 1,61-1,68 (м, 1H), 1,83-2,09 (м, 3H), 2,13-2,19 (м, 1H), 2,28-2,34 (м, 1H), 2,75 (д, J=11,6 Гц, 1H), 3,03 (шир.д, J=11,6 Гц, 1H), 3,31-3,37 (м, 5H), 3,96 (д, J=6,8 Гц, 1H), 4,68 (шир.с, 1H), 4,90 (д, J=11,6 Гц, 1H), 5,05 (д, J=11,6 Гц, 1H), 7,26-7,43 (м, 5H), 9,06-9,20 (м, 1H); MS m/z 461 [M+H] ⁺

Stage 2

tert-Butyl (3R)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate

Following the procedure of Example 17, from the compound (805 mg, 1.75 mmol) of Step 1 above, the title compound was obtained (quantitative yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,46 (с, 9H), 1,75-2,12 (м, 4H), 2,15-2,28 (м, 2H), 3,06 (д, J=11,6 Гц, 1H), 3,13 (шир.д, J=11,6 Гц, 1H), 3,25-3,50 (м, 2H), 3,60 (шир.д, J=12,8 Гц, 1H), 3,70 (шир.с, 1H), 3,87 (шир.д, J=7,2 Гц, 1H), 4,34-4,38 (м, 1H), 4,56-4,63 (м, 1H); MS m/z 371 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[(3R)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl (3R)-1-carboxylate was obtained (quantitative yield). MS m/z 449 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 204.7 mg of the title compound (3 steps, 33% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.67-1.88 (m, 2H), 1.92-2.15 (m, 3H), 2.17-2.26 (m, 1H), 3.02 (d, J=12.0 Hz, 1H), 3.20 (brd, J=12.0 Hz, 1H), 3.27-3.44 (m, 3H), 3.48 (d, J=12.8 Hz, 1H), 3.96 (brd, J=7.2 Hz, 1H), 4.06-4.11 (m, 1H), 4.69-4.74 (m, 1H); MS m/z 349 [MH] ^- .

Example 81

(2S,5R)-7-Oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (II-081)

Stage 1

tert-Butyl (3S)-3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 553 mg, 2.00 mmol) from Example 9 or 16 and (S)-tert-butyl 3-(aminooxy)pyrrolidine-1-carboxylate (606 mg) described in Reference Example 24, 920.4 mg of the title compound was obtained (quantitative yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,46 (с, 9H), 1,61-1,68 (м, 1H), 1,89-2,09 (м, 3H), 2,15-2,19 (м, 1H), 2,28-2,34 (м, 1H), 2,75 (д, J=11,6 Гц, 1H), 2,95-3,06 (м, 1H), 3,31 (шир.с, 1H), 3,35-3,68 (м, 4H), 3,97 (д, J=7,6 Гц, 1H), 4,60 (шир.д, J=23,2 Гц, 1H), 4,90 (д, J=11,6 Гц, 1H), 5,05 (д, J=11,6 Гц, 1H), 7,26-7,43 (м, 5H), 9,08 (шир.д, J=2 3,2 Гц, 1H); MS m/z 461 [M+H] ⁺ .

Stage 2

tert-Butyl (3S)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate

Following the procedure of Example 17, from the compound (869 mg, 1.89 mmol) of Step 1 above, the title compound was obtained (quantitative yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,47 (с, 9H), 1,75-2,12 (м, 4H), 2,13-2,25 (м, 2H), 3,05 (д, J=12,0 Гц, 1H), 3,13 (шир.д, J=12,0 Гц, 1H), 3,25-3,50 (м, 2H), 3,61 (шир.д, J=13,2 Гц, 1H), 3,70 (шир.с, 1H), 3,86 (шир.д, J=7,2 Гц, 1H), 4,32-4,38 (м, 1H), 4,54-4,62 (м, 1H); MS m/z 371 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the same procedure as in Example 59, from the total amount of the compound from Step 2 above, tetrabutylammonium tert-butyl (3S)-1-carboxylate (quantitative yield) was obtained MS m/z 449 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 170.7 mg of the title compound (3 steps, 26% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.71-1.92 (m, 2H), 1.95-2.18 (m, 3H), 2.21-2.30 (m, 1H), 3.07 (d, J=12.2 Hz, 1H), 3.24 (brd, J=12.2 Hz, 1H), 3.31-3.45 (m, 3H), 3.51 (d, J=13.6 Hz, 1H), 3.99 (brd, J=6.0 Hz, 1H), 4.10-4.14 (m, 1H), 4.72-4.77 (m, 1H); MS m/z 349 [MH] ^- .

Example 82

(2S,5R)-N-(Azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (II-082 )

Stage 1

tert-butyl 3-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate

Following the procedure of Example 45, from the carboxylic acid (6b, 553 mg, 2.00 mmol) from Example 9 or 16 and tert-butyl 3-((aminooxy)methyl)azetidine-1-carboxylate (564 mg) described in Reference Example 25, 699.7 mg of the title compound was obtained (76% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,43 (с, 9H), 1,54-1,70 (м, 1H), 1,87-2,06 (м, 2H), 2,27-2,35 (м, 1H), 2,75 (д, J=11,6 Гц, 1H), 2,80-2,90 (м, 1H), 3,01 (шир.д, J=11,6 Гц, 1H), 3,32 (шир.с, 1H), 3,68-3,76 (м, 2H), 3,94 (шир.д, J=7,6 Гц, 1H), 4,00-4,15 (м, 4H), 4,90 (д, J=11,8 Гц, 1H), 5,05 (д, J=11,8 Гц, 1H), 7,35-7,44 (м, 5H), 9,08 (шир.с, 1H); MS m/z 461 [M+H] ⁺ .

Stage 2

tert-Butyl 3-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate

Following the procedure of Example 17, from the compound (642 mg, 1.39 mmol) of Step 1 above, the title compound was obtained (quantitative yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,43 (с, 9H), 1,74-1,85 (м, 1H), 1,86-1,97 (м, 1H), 2,04-2,13 (м, 1H), 2,16-2,24 (м, 1H), 2,84-2,94 (м, 1H), 3,05 (д, J=11,6 Гц, 1H), 3,13 (шир.д, J=11,6 Гц, 1H), 3,68-3,82 (м, 3H), 3,83 (шир.д, J=6,8 Гц, 1H), 3,97-4,06 (м, 4H); MS m/z 371 [M+H] ⁺ .

Stage 3

(2S,5R)-N-(Azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl 3-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate tetrabutylammonium is obtained (quantitative yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,01 (т, J=7,2 Гц, 12H), 1,37-1,51 (м, 8H), 1,46 (с, 9H), 1,54-1,75 (м, 9H), 1,82-1,97 (м, 1H), 2,13-2,25 (м, 1H), 2,29-2,40 (м, 1H), 2,77-2,95 (м, 2H), 3,24-3,40 (м, 9H), 3,64-4,16 (м, 7H), 4,36 (шир.с, 1H), 9,16 (шир.с, 1H); MS m/z 449 [M-Bu ₄ N] ^- .

The total amount of the tetrabutylammonium salt obtained above was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 164.7 mg of the title compound (3 steps, 34% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.65-1.89 (m, 2H), 1.92-2.06 (m, 2H), 3.06 (d, J=12.4 Hz, 1H), 3.10-3.22 (m, 2H), 3.90-4.00 (m, 5H), 4.07-4.14 (m, 3 H); MS m/z 351 [M+H] ⁺ .

Example 83

(2S,5R)-7-Oxo-N-[(3R)-piperidin-3-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl (3R)-3-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and (R)-tert-butyl 3-((aminooxy)methyl)piperidine-1-carboxylate (527 mg, prepared according to the procedure of Reference Example 7 and Reference Example 13), 333 mg of the title compound was obtained (48% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.15-2.10 (m, 8H), 1.45 (s, 9H), 2.25-2.40 (m, 1H), 2.70-3.08 (m, 4H), 3.27-3.37 (m, 1H), 3.65-4.00 (m, 5H), 4.90 (d, J=11.2 Hz, 1H), 5.05 (d, J=11.2 Hz, 1H), 7.34-7.46 (m, 5H), 9.22 (br s, 1H); MS m/z 489 [M+H] ⁺ .

Stage 2

tert-Butyl (3R)-3-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,24-1,37 (м, 1H), 1,40-1,56 (м, 1H), 1,45 (с, 9H), 1,64-1,73 (м, 1H), 1,75-2,00 (м, 4H), 2,03-2,13 (м, 1H), 2,15-2,26 (м, 1H), 2,65-2,95 (м, 2H), 3,06 (д, J=12,0 Гц, 1H), 3,13 (шир.д, J=12,0 Гц, 1H), 3,67-3,91 (м, 5H), 4,01-4,08 (м, 1H); MS m/z 399 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[(3R)-piperidin-3-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the same procedure as in Example 59, from the total amount of the compound from Step 2 above, tetrabutylammonium tert-butyl (3R)-1-carboxylate was obtained (quantitative yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.01 (dd, J=7.6, 6.8 Hz, 12H), 1.11-1.99 (m, 23H), 1.46 (s, 9H), 2.12-2.24 (m, 1H), 2.30-2.42 (m, 1H), 2.67-2.96 (m , 3H), 3.19-3.38 (m, 9H), 3.70-3.99 (m, 5H), 4.35 (br s, 1H), 9.16 (br s, 1H); MS m/z 477 [M-Bu ₄ N] ^- .

The total amount of the above tetrabutylammonium salt was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 106 mg of the title compound (3 steps, 41% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,16-1,28 (м, 1H), 1,54-1,88 (м, 5H), 1,92-2,16 (м, 3H), 2,72 (т, J=12,2 Гц, 1H), 2,81 (ддд, J=12,8, 12,8, 3,5 Гц, 1H), 3,02 (д, J=12,0 Гц, 1H), 3,15-3,28 (м, 2H), 3,37-3,44 (м, 1H), 3,70 (дд, J=10,3, 7,6 Гц, 1H), 3,79 (дд, J=10,3, 5,0 Гц, 1H), 3,88-3,94 (м, 1H), 4,06-4,10 (м, 1H); MS m/z 377 [MH]-.

Example 84

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

Stage 1

tert-Butyl 4-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 552 mg, 2.00 mmol) from Example 9 or 16 and tert-butyl 4-(aminooxy)piperidine-1-carboxylate (1.08 g, prepared according to the procedure of Reference Example 7 and Reference Example 13), 688.5 mg of the title compound was obtained (72.5% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,43 (с, 9H), 1,58-1,66 (м, 5H), 1,85-2,02 (м, 2H), 2,27 (м, 1H), 2,75-2,77 (шир.д, J=11,6 Гц, 1H), 2,99-3,02 (д, J=11,6 Гц, 1H), 3,07-3,13 (м, 2H), 3,29 (с, 1H), 3,71-3,77 (м, 2H), 3,94-3,96 (д, J=7,2 Гц, 1H), 3,98-4,08 (м, 1H), 4,86-4,90 (д, J=11,2 Гц, 1H), 5,01-5,05 (д, J=11,2 Гц, 1H), 7,34-7,41 (м, 5H), 9,02 (шир.с, 1H); MS m/z 475 [M+H] ⁺ .

Stage 2

tert-Butyl 4-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative). MS m/z 385 [M+H]+.

Stage 3

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

Following the procedure of Example 17, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl 4-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate tetrabutylammonium is obtained (quantitative yield). MS m/z 463 [M-Bu ₄ N] ^- .

The total amount of the tetrabutylammonium salt obtained above was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 216.3 mg of the title compound (40.9% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.69-2.08 (m, 8H), 2.99-3.06 (m, 3H), 3.18-3.21 (d, J=12.0 Hz, 1H), 3.26-3.31 (m, 2H), 3.96-3.97 (d, J=3.2 Hz, 1H), 4, 08-4.12 (m, 2H); MS m/z 365 [M+H] ⁺ .

Example 85

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

Stage 1

tert-Butyl 4-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and tert-butyl 4-((aminooxy)methyl)piperidine-1-carboxylate (749 mg, prepared according to the procedure of Reference Example 7 and Reference Example 13), 360.3 mg of the title compound was obtained (52% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,12-1,30 (м, 2H), 1,45 (с, 9H), 1,55-1,69 (м, 1H), 1,70-1,79 (м, 2H), 1,80-2,07 (м, 3H), 2,27-2,38 (м, 1H), 2,60-2,80 (м, 2H), 2,76 (д, J=11,8 Гц, 1H), 3,01 (шир.д, J=11,8 Гц, 1H), 3,31 (шир.с, 1H), 3,68-3,83 (м, 2H), 3,94 (шир.д, J=7,2 Гц, 1H), 4,02-4,20 (м, 2H), 4,91 (д, J=11,4 Гц, 1H), 5,05 (д, J=11,4 Гц, 1H), 7,35-7,44 (м, 5H), 9,04 (шир.с, 1H); MS m/z 489 [M+H] ⁺ .

Stage 2

tert-Butyl 4-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,11-1,23 (м, 2H), 1,45 (с, 9H), 1,74-1,97 (м, 5H), 2,02-2,11 (м, 1H), 2,15-2,23 (м, 1H), 2,66-2,88 (м, 2H), 3,06 (д, J=11,2 Гц, 1H), 3,09-3,16 (м, 1H), 3,67-3,76 (м, 3H), 3,82 (шир.д, J=6,8 Гц, 1H), 4,07 (шир.д, J=13,6 Гц, 2H); MS m/z 399 [M+H] ⁺

Stage 3

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

Following the procedure of Example 17, from the total amount of the compound from the above step 2, 504 mg of tetrabutylammonium tert-butyl 4-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate tetrabutylammonium is obtained (95% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,01 (т, J=7,2 Гц, 12H), 1,17-1,82 (м, 21H), 1,43 (с, 9H), 1,82-1,95 (м, 2H), 2,12-2,22 (м, 1H), 2,31-2,40 (м, 1H), 2,63-2,78 (м, 2H), 2,84 (д, J=12,0 Гц, 1H), 3,16-3,38 (м, 9H), 3,70-3,86 (м, 2H), 3,91 (шир.д, J=7,6 Гц, 1H), 4,00-4,19 (м, 2H), 4,34 (шир.с, 1H), 9,15 (шир.с, 1H); MS m/z 477 [M-Bu ₄ N] ^- .

The total amount of the tetrabutylammonium salt obtained above was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 103 mg of the title compound (3 steps, 37% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.30-1.46 (m, 2H), 1.68-2.11 (m, 7H), 2.85-2.95 (m, 2H), 3.03 (d, J=12.0 Hz, 1H), 3.19 (brd, J=12.0 Hz, 1H), 3.34 (brd, J=12.0 Hz, 2H), 3.73 (d, J=6.0 Hz, 2H), 3.93 (d, J=7.2 Hz, 1H), 4.06-4.14 (m, 1H); MS m/z 377 [MH] ^- .

Example 86

(2S,5R)-N-[2-(1H-Imidazol-1-yl)ethoxy]7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 45, from the carboxylic acid (6b, 552 mg, 2.00 mmol) from Example 9 or 16 and O-(2-(1H-imidazol-1-yl)ethyl)hydroxylamine (386 mg, prepared by the method of Reference Example 7 and Reference Example 13), 770 mg of the title compound was obtained (quantitative yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,70-1,71 (м, 1H), 1,81-1,96 (м, 2H), 2,09-2,14 (м, 1H), 2,90-2,93 (шир.д, J=11,6 Гц, 1H), 3,14 (м, 1H), 3,80-3,85 (м, 2H), 4,12 (м, 1H), 4,22-4,35 (м, 2H), 4,85-4,96 (дд, J=11,2 Гц, 2H), 7,05 (с, 1H), 7,22-7,41 (м, 6H), 8,05 (с, 1H); MS m/z 386 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative). MS m/z 296 [M+H] ⁺ .

Stage 3

(2S,5R)-N-[2-(1H-Imidazol-1-yl)ethoxy]7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Following the procedure of Example 18, pyridinium (2S,5R)-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium is obtained from the total amount of the compound from the above step 2, and is neutralized with saturated aqueous sodium bicarbonate solution and then purified by column chromatography with octadecyl silica gel to give 63.6 mg of the title compound (8.00% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.66-1.85 (m, 2H), 1.97-2.09 (m, 2H), 2.94-2.97 (d, J=12.0 Hz, 1H), 3.14-3.17 (d, J=11.6 Hz, 1H), 3.87-3.89 (d, J=7.2 Hz , 1H), 4.07 (s, 1H), 4.13-4.15 (m, 2H), 4.23-4.26 (m, 2H), 7.00 (s, 1H), 7.19 (s, 1H), 7.86 (s, 1H); MS m/z 376 [M-Na+2H] ⁺ .

Example 87

(2S,5R)-7-Oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 27, from the carboxylic acid (6b, 690 mg, 2.50 mmol) from Example 9 or 16 and O-(2-(1H-pyrrol-1-yl)ethyl)hydroxylamine (450.5 mg, prepared according to the procedure of Reference Example 7 and Reference Example 15), 506 mg of the title compound was obtained (52.6% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,60-1,65 (м, 1H), 1,87-2,03 (м, 2H), 2,26-2,31 (м, 1H), 2,66-2,69 (д, J=11,6 Гц, 1H), 2,93-2,96 (шир.д, J=11,6 Гц, 1H), 3,29 (шир.с, 1H), 3,88-3,90 (д, J=7,6 Гц, 1H), 4,09-4,23 (м, 4H), 4,87-4,90 (д, J=11,6 Гц, 1H), 5,02-5,05 (д, J=11,6 Гц, 1H), 6,17 (с, 2H), 6,71 (с, 2H), 7,33-7,43 (м, 5H); MS m/z 385 [M+H ] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative). MS m/z 295 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Following the procedure of Example 22, pyridinium (2S,5R)-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium is obtained from the total amount of the compound from the above step 2, and is neutralized with saturated aqueous sodium bicarbonate solution and then purified by column chromatography with approx. tadecyl silica gel to give 153 mg of the title compound (29.4% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.64-1.83 (m, 2H), 1.91-2.08 (m, 2H), 2.91-2.94 (d, J=12.0 Hz, 1H), 3.13-3.16 (brd, J=12.0 Hz, 1H), 3.87-3.89 (d, J=11 .6 Hz, 1H), 4.05-4.09 (m, 5H), 6.17 (s, 2H), 6.74 (s, 2H); MS m/z 375 [M-Na+2H] ⁺ .

Example 88

Disodium 1-{2-[({[(2S,5R)-7-oxo-6-(sulfonoxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1H-imidazole-2-sulfonate disodium

The fraction obtained after purification by octadecyl silica gel column chromatography in Example 86, Step 3 gave 71.6 mg of the title compound (7.16% yield).

¹ H ЯМР (400 МГц, D ₂ O): δ 1,66-1,73 (м, 1H), 1,76-1,86 (м, 1H), 1,92-2,08 (м, 2H), 2,96-2,99 (д, J=12,0 Гц, 1H), 3,17-3,20 (д, J=12,4 Гц, 1H), 3,92-3,94 (д, J=8,0 Гц, 1H), 4,07-4,08 (д, J=3,2 Гц, 1H), 4,22-4,24 (м, 2H), 4,41-4,44 (м, 2H), 7,53 (с, 1H), 7,61 (с, 1H); MS m /z 456 [M-2Na+3H] ⁺ .

Example 89

(2S,5R)-N-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 45, from the carboxylic acid (6b, 552 mg, 2.00 mmol) from Example 9 or 16 and 2-(aminooxy)-N,N-dimethylacetamide (244 mg, Huhu Technology), 269.2 mg of the title compound was obtained (46% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,50-1,70 (м, 1H), 1,87-2,10 (м, 2H), 2,24-2,37 (м, 1H), 2,78 (д, J=12,0 Гц, 1H), 2,91 (с, 3H), 2,97 (с, 3H), 3,03 (шир.д, J=12,0 Гц, 1H), 3,26-3,32 (м, 1H), 3,90-3,96 (м, 1H), 4,50-4,67 (м, 2H), 4,90 (д, J=11,4 Гц, 1H), 5,04 (д, J=11,4 Гц, 1H), 7,35-7,45 (м, 5H), 10,04 (шир.с, 1H); MS m/z 377 [M+H] ⁺ .

Stage 2

(2S,5R)-N-[2-(Dimethylamino)-2-oxoethoxy]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.73-1.84 (m, 1H), 1.85-1.99 (m, 1H), 2.02-2.12 (m, 1H), 2.16-2.26 (m, 1H), 2.95 (s, 3H), 3.02-3.15 (m, 2H), 3.05 (s, 3H), 3.67-3.73 (m, 1H), 3.85 (brd, J=7.2 Hz, 1H), 4.57-4.68 (m, 2H); MS m/z 287 [M+H] ⁺ .

Stage 3

(2S,5R)-N-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Following the procedure of Example 18, pyridinium (2S,5R)-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium is obtained from the total amount of the compound from the above step 2 and neutralized with saturated aqueous sodium bicarbonate solution and then purified by column chromatography with ca. tadecyl silica gel to give 180.0 mg of the title compound (2 steps, 65% yield).

¹ H NMR (500 MHz, D ₂ O): δ 1.72-1.85 (m, 2H), 1.89-2.20 (m, 2H), 2.86 (s, 3H), 2.99 (s, 3H), 3.11 (brd, J=11.8 Hz, 1H), 3.28 (brd, J=11.8 Hz, 1H), 3.76-3.81 (m, 1H), 4.08-4.12 (m, 1H), 4.49 (s, 2H); MS m/z 367 [M-Na+2H] ⁺ .

Example 90

(2S,5R)-7-Oxo-N-[2-oxo-2-(piperazin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl 4-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}piperazine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 552 mg, 2.00 mmol) from Example 9 or 16 and tert-butyl 4-(2-(aminooxy)acetyl)piperazine-1-carboxylate (686.2 mg, prepared according to the procedure of Reference Example 14 and Reference Example 15), 499.8 mg of the title compound was obtained (48.3% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,43 (с, 9H),1,67 (м, 1H), 1,90-2,04 (м, 2H), 2,26-2,31 (м, 1H), 2,75-2,78 (д, J=11,6 Гц, 1H), 3,01-3,04 (д, J=11,6 Гц, 1H), 3,33 (м, 3H), 3,45 (м, 4H), 3,58 (м, 2H), 3,92-3,94 (д, J=11,2 Гц, 1H), 4,53-4,56 (д, J=14,4 Гц, 1H), 4,60-4,63 (д, J=14,4 Гц, 1H), 4,88-4,92 (д, J=11,6 Гц, 1H), 5,02-5,07 (д, J=11,6 Гц, 1H), 7,26-7,43 (м, 5H); MS m/z 518 [M+H] ⁺ .

Stage 2

tert-Butyl 4-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}piperazine-1-carboxylate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative). MS m/z 428 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[2-oxo-2-(piperazin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 17, from the total amount of the compound from the above step 2, tetrabutylammonium tert-butyl 4-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}piperazine-1-carboxylate tetrabutylammonium is obtained (quantitative yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,00 (м, 12H), 1,40 (м, 8H), 1,43 (с, 9H),1,62 (м, 8H), 1,84-1,94 (м, 1H), 2,08 (м, 1H), 2,16-2,20 (м, 1H), 2,29-2,34 (м, 1H), 2,81-2,84 (д, J=12,0 Гц, 1H), 3,35-3,37 (м, 3H), 3,45 (м, 4H), 3,54 (м, 2H), 3,89-3,92 (д, J=12,4 Гц, 1H), 4,09-4,14 (м, 8H), 4,31 (шир.с, 1H), 4,51-4,59 (д, J=14,4 Гц, 1H), 4,61-4,65 (д, J=14,4 Гц, 1H); MS m/z 508 [M-Bu ₄ N+H] ⁺ .

The total amount of the tetrabutylammonium salt obtained above was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 149.8 mg of the title compound (38.1% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.17-1.89 (m, 2H), 1.96-2.12 (m, 2H), 3.05-3.08 (d, J=12.4 Hz, 1H), 3.19-3.26 (dt, J=5.2, 16.8 Hz, 4H), 3.22 (m, 1H), 3.68-3.75 (dt, J=5.2, 16.8 Hz, 4H), 3.94-3.96 (d, J=5.6 Hz, 1H), 4.11-4.12 (br s, 1H), 4.61-4.68 (m, 2H); MS m/z 408 [M+H] ⁺ .

Example 91

(2S,5R)-N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 27, from the carboxylic acid (6b, 690 mg, 2.50 mmol) from Example 9 or 16 and 2-(aminooxy)-1-morpholinoethanone (641 mg, prepared according to the procedure of Reference Example 14 and Reference Example 15), 941.9 mg of the title compound was obtained (90.0% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,61-1,66 (м, 1H), 1,91-2,04 (м, 2H), 2,21-2,31 (м, 1H), 2,77-2,79 (д, J=11,6 Гц, 1H), 2,96-2,97 (д, J=4,4 Гц, 1H), 3,01-3,04 (шир.д, J=11,2 Гц, 1H), 3,29-3,38 (м, 4H), 3,57-3,70 (м, 4H), 3,92-3,94 (д, J=7,2 Гц, 1H), 4,52-4,66 (дд, J=11,6,1 4,4 Гц, 2H), 4,87-4,91 (д, J=11,6 Гц, 1H), 5,02-5,05 (д, J=11,6 Гц, 1H), 7,36-7,47 (м, 5H); MS m/z 419 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative). MS m/z 329 [M+H] ⁺ .

Stage 3

(2S,5R)-N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Following the procedure of Example 22, pyridinium (2S,5R)-[2-(morpholin-4-yl)-2-ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium is obtained from the total amount of the compound from the above step 2 and is neutralized with saturated aqueous sodium bicarbonate solution and then purified by column chromatography with octadecyl silica gel to give 152 mg of the title compound (15.7% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.67-1.85 (m, 2H), 1.92-2.04 (m, 2H), 3.00-3.03 (d, J=12.0 Hz, 1H), 3.15-3.18 (d, J=12.0 Hz, 1H), 3.37-3.47 (m, 4H), 3 .60-3.62 (m, 4H), 3.90-3.92 (d, J=6.4 Hz, 1H), 4.6 (br s, 1H), 4.62-4.68 (m, 2H); MS m/z 409 [M-Na+2H] ⁺ .

Example 92

(2S,5R)-N-[2-(1,4-Diazepan-1-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1

tert-Butyl 4-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}-1,4-diazepine-1-carboxylate

Following the procedure of Example 27, from the carboxylic acid (6b, 690 mg, 2.50 mmol) from Example 9 or 16 and t-butyl 4-(2-(aminooxy)acetyl)-1,4-diazepine-1-carboxylate (1.298 g) described in Reference Example 15, 517.6 mg of the title compound was obtained (38.9% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.44 (s, 9H), 1.58 (m, 1H), 1.83-1.96 (m, 3H), 2.27 (m, 1H), 2.75 (m, 1H), 2.99 (m, 1H), 3.30-3.80 (m, 9H), 3.90 (br. s, 1H), 4.58 (m, 2H), 4.88 (m, 1H), 5.03 (m, 1H), 7.24-7.37 (m, 5H); MS m/z 532 [M+H] ⁺ .

Stage 2

tert-Butyl 4-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}-1,4-diazepine-1-carboxylate

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative). MS m/z 442 [M+H] ⁺ .

Stage 3

(2S,5R)-N-[2-(1,4-Diazepan-1-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 17, from the total amount of the compound from the above step 2, tert-butyl 4-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}-1,4-diazepine-1-carboxylate tetrabutylammonium (quantitative yield) is obtained. MS m/z 520 [M-Bu ₄ N] ^- .

The above tetrabutylammonium salt (742.4 mg, 0.973 mmol) was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 153.1 mg of the title compound (37.3% yield).

¹ H ЯМР (400 МГц, D ₂ O): δ 1,71-1,89 (м, 2H), 1,97-2,16 (м, 4H), 3,06-3,10 (д, J=12,0 Гц, 1H), 3,19-3,22 (д, J=12,4 Гц, 1H), 3,25-3,29 (м, 3H), 3,36-3,39 (м, 2H), 3,50-3,60 (м, 2H), 3,73-3,75 (м, 2H), 3,94-3,95 (д, J=7,2 Гц, 1H), 4,11 (с, 1H), 4,62-4,69 (м, 2H); MS m/z 422 [M+H] ⁺ .

Example 93

(2S,5R)-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 27, from the carboxylic acid (6b, 550 mg, 2.00 mmol) from Example 9 or 16 and 1-(2-(aminooxy)ethyl)pyrrolidin-2-one (518.4 mg), 699.5 mg of the title compound was obtained (86.9% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,60-1,66 (м, 1H), 1,92-2,11 (м, 4H), 2,26-2,31 (м, 1H), 2,40-2,44 (м, 2H), 2,78-2,81 (шир.д, J=12,0 Гц, 1H), 3,06-3,09 (д, J=11,6 Гц, 1H), 3,27 (шир.с, 1H), 3,33-3,38 (м, 1H), 3,44-3,54 (м, 2H), 3,68-3,74 (м, 1H), 3,94-4,14 (м, 3H), 4,87-4,90 (д, J=11,2 Гц, 1H), 5,02-5,04 (д, J=11,2 Гц, 1H), 7,26-7,42 (м, 5H), 10,10 (шир.с, 1H); MS m/z 403 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative). MS m/z 313 [M+H] ⁺ .

Stage 3

(2S,5R)-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Following the procedure of Example 22, pyridinium (2S,5R)-7-oxo-N-[2-(oxopyrrolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium is obtained from the total amount of the compound from the above step 2, and is neutralized with saturated aqueous sodium bicarbonate solution and then purified by column chromatography with octadecyl silica gel to give 460.6 mg of the title compound (64.2% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.67-1.73 (m, 1H), 1.79-1.87 (m, 1H), 1.90-2.06 (m, 4H), 2.30-2.34 (t, J=8.4 Hz, 1H), 3.01-3.08 (d, J=12.4 Hz, 1H), 3, 19-3.22 (d, J=12.0 Hz, 1H), 3.38-3.50 (m, 4H), 3.93-3.99 (m, 3H), 4.09 (br s, 1H); MS m/z 393 [M-Na+2H] ⁺ .

Example 94

(2S,5R)-7-Oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 45, from the carboxylic acid (6b, 390 mg, 1.41 mmol) from Example 9 or 16 and 1-(2-(aminooxy)ethyl)imidazolidin-2-one (512 mg, prepared according to the procedure of Reference Example 7 and Reference Example 15), 347 mg of the title compound was obtained (61% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,50-1,68 (м, 1H), 1,91-2,06 (м, 2H), 2,24-2,35 (м, 1H), 2,80 (д, J=12,0 Гц, 1H), 3,06 (шир.д, J=12,0 Гц, 1H), 3,21-3,39 (м, 2H), 3,40-3,68 (м, 5H), 3,92-4,06 (м, 3H), 4,32 (шир.с, 1H), 4,89 (д, J=11,6 Гц, 1H), 5,04 (д, J=11,6 Гц, 1H), 7,33-7,44 (м, 5H), 10,10 (шир.с, 1H); MS m/z 404 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.74-1.84 (m, 1H), 1.87-2.13 (m, 2H), 2.16-2.27 (m, 1H), 3.04 (d, J=11.6 Hz, 1H), 3.11-3.18 (m, 1H), 3.27-3.49 (m, 4H), 3.58-3.66 (m, 2H), 3.67-3.73 (m, 1H), 3.85 (brd, J=7.6 Hz, 1H), 3.92-4.05 (m, 2H); MS m/z 314 [M+H] ⁺ .

Stage 3

(2S,5R)-7-Oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

To a solution of the total compound from Step 2 above in methylene chloride (8.6 ml) was added 2,6-lutidine (300 μl) and sulfur trioxide-pyridine complex (410 mg) and the mixture was stirred at room temperature overnight. Methylene chloride was added to the reaction solution, which was then filtered and concentrated under reduced pressure. An aqueous solution of sodium bicarbonate was added to the obtained 486.7 mg of (2S,5R)-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium, followed by lyophilization. Get the crude product. The resulting crude product was purified by octadecyl silica gel column chromatography to give 36.8 mg of the title compound (2 steps, 10% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.59-2.08 (m, 4H), 3.02 (d, J=12.6 Hz, 1H), 3.18 (brd, J=12.6 Hz, 1H), 3.27-3.49 (m, 4H), 3.59-3.67 (m, 2H), 3.90-3.98 (m, 3H), 4.05-4.10 (m, 1H); MS m/z 394 [M-Na+2H] ⁺ .

Example 95

(2S,5R)-N-(2-Hydroxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-7-oxo-N-(2-triisopropylsilyloxyethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 45, from the carboxylic acid (6b, 553 mg, 2.00 mmol) from Example 9 or 16 and O-(2-((triisopropylsilyl)oxy)ethyl)hydroxylamine (630 mg, prepared according to the method of Reference Example 15 from the compound of Reference Example 12), 695.0 mg of the title compound was obtained (71% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,00-1,20 (м, 21H), 1,57-1,70 (м, 1H), 1,88-2,10 (м, 2H), 2,28-2,37 (м, 1H), 2,78 (д, J=11,6 Гц, 1H), 2,98 (шир.д, J=11,6 Гц, 1H), 3,31 (шир.с, 1H), 3,87-4,08 (м, 5H), 4,90 (д, J=11,4 Гц, 1H), 5,05 (д, J=11,4 Гц, 1H), 7,35-7,45 (м, 5H), 9,38 (шир.с, 1H); MS m/z 492 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-7-oxo-N-(2-triisopropylsilyloxyethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the same procedure as in Example 17, from the total amount of the compound from Step 1 above, 530.7 mg of the title compound was obtained (94% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.00-1.20 (m, 21H), 1.74-1.85 (m, 1H), 1.86-1.99 (m, 1H), 2.01-2.13 (m, 1H), 2.15-2.25 (m, 1H), 3.06 (d, J=1 1.6 Hz) , 1H), 3.12 (brd, J=11.6 Hz, 1H), 3.69 (br s, 1H), 3.82 (brd, J=7.2 Hz, 1H), 3.90-4.01 (m, 4H); MS m/z 402 [M+H] ⁺ .

Stage 3

(2S,5R)-N-(2-Hydroxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Following the procedure of Example 59, from the total amount of the compound from the above step 2, tetrabutylammonium (2S,5R)-7-oxo-6-(sulfooxy)-N-(2-triisopropylsilyloxyethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide tetrabutylammonium was obtained (quantitative yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.87-1.19 (m, 33H), 1.36-1.98 (m, 18H), 2.13-2.23 (m, 1H), 2.31-2.42 (m, 1H) 2.85 (brd, J=11.6 Hz, 1H), 3.21-3.38 (m, 9H), 3.83-4.17 (m, 5H), 4.35 (br s, 1H), 9.37 (br s, 1H); MS m/z 480 [M-Bu ₄ N] ^- .

The total amount of the tetrabutylammonium salt obtained above was subjected to a deprotection reaction using trifluoroacetic acid and purified by octadecyl silica gel column chromatography to obtain 140.2 mg of the title compound (3 steps, 29% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.65-1.88 (m, 2H), 1.91-2.08 (m, 2H), 3.04 (d, J=12.0 Hz, 1H), 3.18 (brd, J=12.0 Hz, 1H), 3.63-3.69 (m, 2H), 3.85-3.96 (m, 3H), 4.05-4.09 (m, 1H); MS m/z 324 [M-Na] ^- .

Example 96

(2S,5R)-N-(2-methoxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N-(2-methoxyethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 45, from the carboxylic acid (6b, 414 mg, 1.50 mmol) from Example 9 or 16 and O-(2-methoxyethyl)hydroxylamine (190 mg, Huhu Technology), 386.7 mg of the title compound was obtained (74% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,57-1,72 (м, 1H), 1,88-2,10 (м, 2H), 2,29-2,37 (м, 1H), 2,78 (д, J=11,8 Гц, 1H), 2,99 (шир.д, J=11,8 Гц, 1H), 3,30 (шир.с, 1H), 3,39 (с, 3H), 3,63 (т, J=4,4 Гц, 2H), 3,95 (шир.д, J=7,6 Гц, 1H), 4,01-4,15 (м, 2H), 4,90 (д, J=11,4 Гц, 1H), 5,05 (д, J=11,4 Гц, 1H), 7,35-7,45 (м, 5H), 9,32 (шир.с, 1H); MS m/z 350 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-N-(2-methoxyethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the same procedure as in Example 17, from the total amount of the compound from Step 1 above, 272.4 mg of the title compound was obtained (95% yield).

¹ H ЯМР (400 МГц, CD ₃ OD): δ 1,74-1,85 (м, 1H), 1,86-1,98 (м, 1H), 2,02-2,12 (м, 1H), 2,16-2,25 (м, 1H), 3,08 (д, J=11,6 Гц, 1H), 3,12 (brd, J=11,6 Гц, 1H), 3,37 (с, 3H), 3,61-3,65 (м, 2H), 3,67-3,72 (м, 1H), 3,82 (шир.д, J=8,4 Гц, 1H), 3,99-4,03 (м, 2H); MS m/z 260 [M+H] ⁺ .

Stage 3

(2S,5R)-N-(2-methoxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Following the procedure of Example 18, pyridinium (2S,5R)-N-(2-methoxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium was obtained from the total amount of the compound from the above step 2 and neutralized with saturated aqueous sodium bicarbonate and then purified by octadecyl silica gel column chromatography to obtain m 247.4 mg of the title compound (2 steps, 62% yield).

¹ H ЯМР (500 МГц, D ₂ O): δ 1,69-1,78 (м, 1H), 1,78-1,88 (м, 1H), 1,93-2,01 (м, 1H), 2,01-2,09 (м, 1H), 3,06 (д, J=12,3 Гц, 1H), 3,20 (шир.д, J=12,3 Гц, 1H), 3,28 (с, 3H), 3,57-3,62 (м, 2H), 3,94 (шир.д, J=6,5 Гц, 1H), 3,94-3,99 (м, 2H), 4,08-4,13 (м, 1H); MS m/z 340 [M-Na+2H] ⁺ .

Example 97

(2S,5R)-N-[2-(methylsulfonyl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

Stage 1

(2S,5R)-6-Benzyloxy-N-[2-(methylsulfonyl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following the procedure of Example 45, from the carboxylic acid (6b, 414 mg, 1.50 mmol) from Example 9 or 16 and O-(2-(methylsulfonyl)ethyl)hydroxylamine (279 mg, Huhu Technology), 293 mg of the title compound was obtained (49% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,44-1,70 (м, 1H), 1,90-2,10 (м, 2H), 2,24-2,36 (м, 1H), 2,74 (д, J=12,0 Гц, 1H), 3,04 (шир.д, J=12,0 Гц, 1H), 3,12 (с, 3H), 3,31-3,39 (м, 3H), 3,96 (шир.д, J=7,6 Гц, 1H), 4,38 (шир.т, J=5,4 Гц, 2H), 4,91 (д, J=11,4 Гц, 1H), 5,05 (д, J=11,4 Гц, 1H), 7,36-7,45 (м, 5H), 9,31 (шир.с, 1H); MS m/z 398 [M+H] ⁺ .

Stage 2

(2S,5R)-6-Hydroxy-N-[2-(methylsulfonyl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Using the same procedure as in Example 17, the title compound was obtained from the total amount of the compound from Step 1 above (yield quantitative).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.77-1.86 (m, 1H), 1.87-1.99 (m, 1H), 2.03-2.13 (m, 1H), 2.17-2.26 (m, 1H), 3.04 (d, J=12.0 Hz, 1H), 3.07-3.18 (m, 4H), 3.46 (t, J=5.6 Hz, 2H), 3.68-3.74 (m, 1H), 3.86 (bd, J=6.4 Hz, 1H), 4.30 (t, J=5.6 Hz, 2H); MS m/z 308 [M+H] ⁺ .

Stage 3

(2S,5R)-N-[2-(methylsulfonyl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium

To a solution of the total compound from Step 2 above in methylene chloride (7.4 ml) was added 2,6-lutidine (257 μl) and sulfur trioxide-pyridine complex (352 mg) and the mixture was stirred at room temperature overnight. The pyridinium (2S,5R)-N-[2-(methylsulfonyl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide pyridinium was neutralized by adding a saturated aqueous sodium bicarbonate solution. The organic solvent is distilled off under reduced pressure, then lyophilized to obtain a crude product. The resulting crude product was purified by octadecyl silica gel column chromatography to give 51.1 mg of the title compound (2 steps, 17% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.65-1.86 (m, 2H), 1.90-2.06 (m, 2H), 3.00-3.10 (m, 1H), 3.05 (s, 3H), 3.06 (d, J=12.0 Hz, 1H), 3.15 (brd, J=12.0 Hz, 1 H), 3.49 (bt, J=5.6 Hz, 2H), 3.86-3.93 (m, 1H), 4.05-4.09 (m, 1H), 4.22 (bt, J=5.6 Hz, 1H); MS m/z 388 [M-Na+2H] ⁺ .

Example 98

(2S,5R)-5-(Benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylic acid (IV-a2)

A solution of (2S,5R)-tert-butyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (1.50 g, 3.73 mmol) in methylene chloride (5.0 ml) was cooled with ice and trifluoroacetic acid (5.0 ml) was added and allowed to react at the same temperature for 30 minutes and then at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, then water and 6.5% sodium bicarbonate aqueous solution were added to the residue. After adjusting the pH to about pH 8, the aqueous layer was washed with ethyl acetate. To this aqueous layer was added a 5% aqueous solution of potassium hydrogen sulfate. After adjusting the pH to about pH 5.6, the aqueous layer was extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 0.913 g of the title compound (71% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ is obtained as a mixture of two rotamers (approximately 6:4). 1.68-1.76(m, 2H), 2.05-2.08(m, 2H), 3.14(d, J=14.4Hz, 0.4H), 3.27(m, 1H), 3.48(m, 0.6H), 4.15(m, 1H), 4.58-4.75(m, 3H), 5.20(m, 1H ), 4.30-4.38 (m, 5H); MS m/z 347 [M+H] ⁺ .

Example 99

(2S,5R)-5-((Benzyloxy)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (IV-a3)

(2S,5R)-5-(Benzyloxyamino)piperidine-2-carboxylic acid dihydrochloride (2.00 g, 6.19 mmol) described in Example 11 was added to 1,4-dioxane (10 ml) and water (15 ml), then 5M aqueous sodium hydroxide solution (3.7 ml) was added and stirred under ice-cooling. Potassium carbonate (854 mg) and di-tert-butoxycarbonyl dicarbonate (1.69 g) were added to the mixture, and the temperature was raised to room temperature, followed by overnight stirring. The resulting solution was concentrated and the aqueous solution was adjusted to pH 3.3 with citric acid monohydrate, then extracted twice with ethyl acetate (20 ml) and washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent is concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate) to obtain 1.879 g of the title compound (87% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.46 (s, 9H), 1.50-1.72 (m, 2H), 1.98-2.10 (m, 2H), 3.12-3.19 (m, 2H), 4.13-4.20 (m, 1H), 4.76 (d, J=11.5 Hz, 1H), 4 .70 (d, J=11.5 Hz, 1H), 4.85-4.92 (m, 1H), 7.26-7.35 (m, 5H); MS m/z 351 [M+H] ⁺ .

Example 100

Sequential synthesis of (2S,5R)-5-((benzyloxy)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (IV-a3)

A solution of (2S,5R)-tert-butyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (66.8 g, 166.0 mmol) described in Example 3 in methylene chloride (135 ml) was cooled on ice and trifluoroacetic acid (135 ml) was added and allowed to react at the same temperature for 3 0 minutes and then at room temperature for 2 hours, and the reaction mixture is concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 ml) and washed with 25% monosodium citrate (200 ml) and brine (200 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 1,4-dioxane (133 ml) and 5M sodium hydroxide (133 ml) was added thereto under ice-cooling and stirred for 1 hour, then the mixture was concentrated under reduced pressure. After washing the aqueous layer with ether (200 ml), the pH was adjusted to pH 10 with 5M hydrochloric acid (55 ml) and potassium carbonate (23 g) and di-t-butyl dicarbonate (44 g) were added, then stirred overnight. The organic solvent from the mixture was concentrated under reduced pressure and the concentrated mixture was washed with ether (200 ml). The aqueous layer was adjusted to pH 3.9 with citric acid and extracted with ethyl acetate (500 ml, 250 ml). The organic layer was washed with brine (250 ml) and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give 48.02 g of the title compound (83% yield). The measurement data for this product correspond to the data from example 99.

Example 101

(2S,5R)-5-((Benzyloxy)amino)-1-(2-trimethylsilylethoxycarbonyl)piperidine-2-carboxylic acid (IV-a4)

To (2S,5R)-5-(benzyloxyamino)-piperidine-2-carboxylic acid dihydrochloride (3.23 g, 10 mmol) described in Example 11 was added 1,4-dioxane (10 ml), water (15 ml) and 5M sodium hydroxide (6 ml) and stirred under ice-cooling. Potassium carbonate (1.38 g), N-(trimethylsilylethyloxycarbonyloxy)succinimide (2.85 g) was added to the mixture, and the temperature was raised to room temperature, followed by overnight stirring. The mixture was adjusted to pH 4 with citric acid monohydrate and extracted twice with ethyl acetate (50 ml). The organic layer is washed with water and brine and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1:1→1:0) to obtain 3.41 g of the title compound (86% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 0.01 (s, 9H), 0.97 (t, J=8.3 Hz, 2H), 1.59-1.68 (m, 2H), 1.97-2.02 (m, 2H), 3.00-3.25 (m, 2H), 4.08-4.19 (m, 3H), 4, 65 (d, J=11.3 Hz, 1H), 4.71 (d, J=11.3 Hz, 1H), 4.72-4.89 (m, 1H), 7.23-7.32 (m, 5H); MS m/z 395 [M+H] ⁺ .

Example 102

(2S,5R)-N-(2-tert-Butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamide (IV-b2-Boc-059)

(2S,5R)-5-(Benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylic acid (0.879 g, 2.54 mmol) described in Example 98 and tert-butyl 2-(aminooxy)ethylcarbamate (0.559 g) from Reference Example 9 were dissolved in N,N-dimethylformamide (11 ml) and added thereto 1-hydroxybenzotriazole monohydrate (0.489 g) under ice-cooling. N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.613 g) was added to the mixture, and the temperature was raised to room temperature, followed by reaction for 3 hours. Water is added to the reaction mixture and extracted with ethyl acetate. After successively washing the organic layer with 10% citric acid aqueous solution, water, 6.5% sodium bicarbonate aqueous solution and brine, and then the solvent was distilled off under reduced pressure. The resulting oily residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2) to obtain 1.07 g of the title compound (84% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ is obtained as a mixture of two rotamers (approximately 7:3). 1.26(m, 0.3H), 1.44(s, 9H), 1.70(m, 0.7H), 1.81-2.12(m, 3H), 3.10(brd, J=14.4Hz, 0.3H), 3.30(m, 3H), 3.54(brd, J=12.4Hz, 0.7H), 3.87 (m, 2H), 4.15 (d, J=13.2 Hz, 0.7H), 4.58-4.79 (m, 2.6H), 4.90 (m, 0.7H), 4.97 (m, 0.3H), 5.11 (m, 0.7H), 5.33 (m, 1H), 7.26-7.38 (m, 5H), 9.7 5 (br s, 0.7H), 10.48 (br s, 0.3H); MS m/z 505 [M+H] ⁺ .

Example 103

(2S,5R)-N-(2-tert-Butoxycarbonylaminoethoxy)-5-(benzyloxy)piperidine-2-carboxamide (IV-c-Boc-059)

(2S,5R)-N-(2-tert-Butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamide (1.07 g, 2.06 mmol) was dissolved in 1,4-dioxane (4.2 ml), water (1.1 ml) was added to the mixture and cooled on ice. A 1M sodium hydroxide aqueous solution (6.3 ml) was added to the mixture, and reacted at the same temperature for 2.5 hours. The pH is adjusted to approximately pH 7 by adding acetic acid to the reaction mixture. The organic solvent is evaporated off under reduced pressure. The resulting aqueous solution is extracted with ethyl acetate. Then, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting oily residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to obtain 0.80 g of the title compound (93% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.36-1.44 (m, 10H), 1.74 (m, 1H), 1.95 (m, 1H), 2.10 (m, 1H), 2.68 (m, 1H), 3.14 (m, 1H), 3.33 (m, 2H), 3.42 (m, 1H), 3.50 (m, 1H), 3.88 (m, 2H), 4.66 (s, 2H), 5.49 (br.m, 1H), 7.29-7.37 (m, 5H); MS m/z 409 [M+H] ⁺ .

Example 104

(2S,5R)-N-(2-tert-Butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-[2-(trimethylsilyl)ethyloxycarbonyl]piperidine-2-carboxamide (IV-b4-059)

(2S,5R)-5-(Benzyloxyamino)-1-((2-(trimethylsilyl)ethoxy)carbonyl)piperidine-2-carboxylic acid (601mg, 1.52mmol) described in Example 101 and tert-butyl 2-(aminooxy)ethylcarbamate (303mg, 1.72mmol) described in Reference Example 9 are dissolved in N,N- dimethylformamide (5.8 ml), 1-hydroxybenzotriazole monohydrate (264 mg) was added, followed by ice-cooling. N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg) was added, the temperature was raised to room temperature and the reaction was carried out for 5 hours. Water is added to the reaction mixture and extracted with ethyl acetate. Then, the organic layer was washed successively with 10% citric acid aqueous solution, water, 6.5% sodium bicarbonate aqueous solution and brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting oily residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2) to obtain 450 mg of the title compound (54% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 0,01 (с, 9H), 0,98 (м, 2H), 1,42 (с, 9H), 1,58 (м, 1H), 1,84-1,96 (м, 3H), 3,04 (м, 1H), 3,18 (шир.с, 1H), 3,28 (м, 1H), 3,35 (м, 1H), 3,85 (м, 2H), 4,16-4,35 (м, 3H), 4,63-4,75 (м, 3H), 5,32-5,70 (шир.м, 2H), 4,26-4,33 (м, 5H), 9,44 (шир.с, 1H); MS m/z 553 [M+H] ⁺ .

Example 105

Synthesis from tert-butyl 2-((2S,5R)-5-(benzyloxyamino)piperidine-2-carboxamide)ethylcarbamate (IV-c-Boc-059): (IV-b4-Boc-059)

(2S,5R)-N-(2-tert-Butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-[2-(trimethylsilyl)ethyloxycarbonyl]piperidine-2-carboxamide (417 mg, 0.754 mmol) was dissolved in tetrahydrofuran (5.5 ml), 1.0 M solution of fluorotetra-n-butylammonium in tetrahydrofuran (1 .9 ml), then the reaction is carried out at 50°C for 24 hours. The reaction mixture was diluted with ethyl acetate, and washed successively with 6.5% sodium bicarbonate aqueous solution, water and brine, then the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting oily residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate/methanol=9/1) to obtain 250 mg of the title compound (81% yield). The measurement data for this product are consistent with those from Example 103.

Example 106

(2S,5R)-N-(2-Benzyloxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(tert-butoxycarbonyl)piperidine-2-carboxamide (IV-c-Cbz-059)

(2S,5R)-5-((Benzyloxy)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (1.879 g, 5.362 mmol) described in Example 99 or 100, benzyl 2-(aminooxy)ethylcarbamate (1.41 g, 6.707 mmol) from Reference Example 11 and 1-hydroxybenzo monohydrate triazole (220 mg) was dissolved in methylene chloride (20 ml), then stirred on ice. N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.29 g) was added thereto, and the temperature was raised to room temperature and stirred overnight. The mixture was diluted successively with methylene chloride (20 ml) and washed successively with water, 10% aqueous citric acid, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give 2.91 g of the title compound (quantitative).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.46 (s, 9H), 1.50-1.93 (m, 4H), 3.40 (m, 2H), 3.89 (m, 2H), 4.15-4.21 (m, 1H), 4.61 (m, 1H), 4.69 (d, J=11.6 Hz, 1H), 4.76 (d, J=11.6 Hz, 1H), 5.11 (s, 2H), 5.86 (s, 1H), 7.27-7.36 (m, 5H), 9.28 (s, 1H); MS m/z 543 [M+H] ⁺ .

Example 107

(2S,5R)-N-(2-Benzyloxycarbonylaminoethoxy)-5-(benzyloxyamino)piperidine-2-carboxamide (IV-c-Cbz-059)

(2S,5R)-N-(2-Benzyloxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(tert-butoxycarbonyl)piperidine-2-carboxamide (2.91 g, 5.362 mmol) was dissolved in 1,4-dioxane (5 ml), 4M hydrochloric acid in dioxane (10 ml) was added under ice-cooling. After stirring for 2 hours, the mixture was concentrated under reduced pressure, dissolved in water (30 ml) and washed with ether. The aqueous layer is cooled with ice and the pH is adjusted to approximately pH 7 with 5M sodium hydroxide and acetic acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform→chloroform/methanol=3:1) to obtain 2.27 g of the title compound (95% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,22-1,34 (м, 1H), 1,50-1,58 (м, 1H), 1,89-1,92 (м, 1H), 1,92-2,06 (м, 1H), 2,43-2,48 (м, 1H), 2,95 (м, 1H), 3,23-3,27 (м, 1H), 3,40-3,42 (м, 2H), 3,71-3,73 (м, 2H), 3,89-3,92 (м, 2H), 4,66 (с, 2H), 5,11 (с, 2H), 5,91 (с, 1H), 7,26-7,52 (м, 10H); MS m/z 443 [M+H] ⁺ .

Example 108

Benzyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate (IIa-Cbz-059)

A solution of (2S,5R)-N-(2-benzyloxycarbonylaminoethoxy)-5-(benzyloxy)piperidine-2-carboxamide (642 mg, 1.451 mmol) in acetonitrile (66 ml) was cooled with ice, triethylamine (709 μl) and chlorotrimethylsilane (203 μl) were added, stirred for 1 hour. Trichloromethyl chloroformate (105 μl) was added to the reaction mixture, and the mixture was stirred at the same temperature for 20 minutes. 4-(Dimethylamino)pyridine (18 mg) was then added to the reaction solution, the temperature was raised to room temperature, and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate, then washed successively with water, 5% aqueous citric acid, 6.5% aqueous sodium bicarbonate and brine. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/3) to obtain 407 mg of the title compound (60% yield).

¹ H ЯМР (400 МГц, CDCl ₃ ): δ 1,59-1,65 (м, 1H), 1,91-2,02 (м, 2H), 2,26-2,31 (м, 1H), 2,71-2,74 (д, J=11,6 Гц, 1H), 2,99-3,02 (шир.д, J=11,2 Гц, 1H), 3,28 (с, 1H), 3,31-3,39 (м, 1H), 3,46-3,49 (м, 1H), 3,88-3,97 (м, 3H), 4,88-4,91 (д, J=11,6 Гц, 1H), 5,03-5,06 (д, J=11,6 Гц, 1H), 5,11 (с, 2H), 5,83 (шир.с, 1H), 7,27-7,43 (м, 10H), 9,36 (шир.с, 1H); MS m/z 469 [M+H] ⁺ .

Example 109

(2S,5R)-N-(2-tert-Butoxycarbonylaminoethoxy)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (IIa-Boc-059)

A solution of (2S,5R)-N-(2-tert-butoxycarbonylaminoethoxy)-5-(benzyloxy)piperidine-2-carboxamide (368 mg, 0.901 mmol) described in Example 103 or 105 in acetonitrile (40.9 ml) was cooled with ice, triethylamine (440 μl) and chlorotrimethylsilane (126 μl) were added ) and the resulting mixture was stirred for 1 hour. Trichloromethyl chloroformate (66.0 µl) was added to the reaction mixture, followed by stirring at the same temperature for 30 minutes. Then, 4-(dimethylamino)pyridine (10.2 mg) was added to the reaction solution, and the temperature was raised to room temperature, and the reaction was carried out for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate, then washed successively with water, 5% citric acid aqueous solution, 6.5% sodium bicarbonate aqueous solution, and brine. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting oily residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/3) to give 202 mg of the title compound as a colorless solid (52% yield). The measurement data for this product is the same as for Example 59.

Example 110

tert-Butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate (IIb-Boc-059)

tert-Butyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate (43.4 g, 100 mmol) was dissolved in tetrahydrofuran (475 ml). After dissolution was confirmed, water (25 ml) was added and allowed to stand under argon. 10% Pd/C (8.68 g, 50% moisture) was added and the mixture was vigorously stirred under a hydrogen atmosphere for 3 hours. The end point was confirmed by TLC and the catalyst was filtered through Celite. The solvent from the filtrate is concentrated under reduced pressure. The concentrated residue was displaced and concentrated twice with ethyl acetate (100 ml) and once with methylene chloride (100 ml) to give 34.5 g of the title compound (yield quantitative). The measurement data for this product is the same as for Example 59.

Example 111

tert-Butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate (IIb-Boc-059): synthesis from (IIa-Cbz-059)

Benzyl {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate (468 mg, 1.00 mmol) described in Example 108 and di-tert-butoxycarbonylbutyl dicarbonate (240 mg) were dissolved in tetrahydrofuran (6.6 ml) and add 10% Pd/C (93 mg, 50% moisture), stir vigorously for 3 hours under a hydrogen atmosphere. The end point was confirmed by TLC and then the catalyst was filtered through Celite. The solvent from the filtrate was concentrated under reduced pressure to give 403.7 mg of the title compound (quantitative). The measurement data for this product is the same as for Example 59.

Example 112

tert-Butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}tetrabutylammonium carbamate (III-Boc-059)

To a solution of tert-butyl {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate (34.5 g, 100 mmol) in methylene chloride (500 ml) was added successively 2,6-lutidine (32.8 g) and a complex of sulfur trioxide - pyridine (51.9 g) and stirred for 24 hours. Completion of the reaction is confirmed by HPLC, the reaction mixture is filtered and the filtrate is added to 8% aqueous sodium bicarbonate solution (1 L) and washed with methylene chloride (500 ml). Ethyl acetate (1 L) was added to the aqueous layer, then tetrabutylammonium hydrogen sulfate (37.34 g) was added, paying attention to foaming, and stirred for 30 minutes. After liquid separation, the aqueous layer was extracted twice with ethyl acetate (500 ml). The combined organic layers were dried over magnesium sulfate and the solvent was concentrated under reduced pressure to give 53.9 g of the title compound (81.1% yield). The measurement data for this product is the same as for Example 59.

Example 113

(2S,5R)-N-(2-Aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (III-059)

A solution of tetrabutylammonium tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate (68.9 g, 104 mmol) in methylene chloride (170 ml) was cooled to -20°C and trifluoroacetic acid was added y (170 ml) at -15°C or less for 20 minutes, then stirred at 0°C for 35 minutes. Diethyl ether (510 ml) was added to the reaction mixture, and the mixture was stirred at 0° C. for 40 minutes. The precipitated solid is filtered through a Kiriyama funnel and washed with diethyl ether (450 ml), then dried in vacuo to give the crude product (39.5 g). The residue was added to 0.5 M sodium acetate/acetic acid buffer (400 ml, pH 5.6) and then adjusted to pH 5.6 with 5 M aqueous sodium hydroxide and then purified by octadecyl silica gel (water) column chromatography to give 24.8 g of the title compound (74% yield). The measurement data for this product is the same as for Example 59.

Example 114

(2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate dihydrochloride (4b); Synthesis from compound (2) via (2S,5S)-5-hydroxypiperidine-2-carboxylic acid hydrochloride (7)

Stage 1

(2S,5S)-5-hydroxypiperidine-2-carboxylic acid hydrochloride (7)

(2S,5S)-tert-Butyl 5-hydroxypiperidine-2-carboxylate (126.22 g, 0.63 mol) described in Example 1 was gradually added to 5M hydrochloric acid (630 ml) at room temperature, then heated to 65°C and stirred for 2 hours. Then, the reaction solution is cooled to room temperature, and the reaction solvent is concentrated under reduced pressure. The residue was dissolved in water (500 ml) and activated charcoal (6.5 g) was added, stirred at room temperature for 30 minutes. Activated charcoal is filtered through Celite. Celite is washed twice with water (100 ml) and the filtrate is combined, then concentrated under reduced pressure. The residue (150 g) is ice-cooled, then inoculated and stirred. Acetone (650 ml) was added dropwise to the mixture over 30 minutes, then stirred for 30 minutes. The precipitated crystals are filtered under a stream of argon, then washed with acetone. After removal of the liquid and drying in vacuo overnight, 108.79 g of the title compound are obtained as colorless powdery crystals (96% yield).

¹ H NMR (400 MHz, D ₂ O): δ 1.66-2.23 (m, 4H), 3.25 (d, J=3.4 Hz, 1H), 3.38 (d, J=3.4 Hz, 1H), 4.00 (dd, J=11.7, 3.7 Hz, 1H), 4.22 (br s, 1H); MS m/z: 146 (M-HCl+H) ⁺ .

Stage 2

(2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate hydrochloride (8)

To (2S,5S)-5-hydroxypiperidine-2-carboxylic acid hydrochloride (26.46 g, 0.146 mol) was added 2M hydrogen chloride-methanol (230 ml), followed by heating under reflux. After 1.5 hours, the reaction solution was concentrated, then replaced and concentrated with methanol (200 ml) three times. The residue was dried in vacuo to give 28.55 g of the title compound as a colorless crystalline powder (quantitative).

¹ H NMR (400 MHz, D ₂ O): δ 1.74-2.06 (m, 4H), 3.12 (dd, J=2.0, 13.2 Hz, 1H), 3.25-3.29 (m, 1H), 3.72 (s, 3H), 3.98 (dd, J=3.8, 12.2 Hz, 1H), 4.09 (broad s, 1H); MS m/z: 160 (M-HCl+H) ⁺ .

Stage 3

(2S,5S)-Methyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (9)

To a suspension of (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate hydrochloride (26.80 g, 0.137 mol) in anhydrous tetrahydrofuran (440 ml) was added triethylamine (91.0 ml) under ice-cooling, then trifluoroacetic acid anhydride (39.5 ml) was added dropwise at 10°C or lower over 1 hour. The reaction suspension is stirred for 70 minutes, gradually increasing the temperature to room temperature. Water (80 ml) was added to the reaction solution, followed by stirring at room temperature for 30 minutes. The mixture is then added to water (1000 ml) and extracted three times with ethyl acetate (500 ml + 2×250 ml). The organic layer was washed with 1M hydrochloric acid (300 ml), saturated aqueous sodium bicarbonate (200 ml), and brine (2×150 ml), dried, and then concentrated under reduced pressure to give 34.65 g of the title compound as an oil (99% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ is obtained as a mixture of two rotamers (approximately 7:3). 1.34-1.44(m, 1H), 1.73-1.83(m, 1H), 2.00-2.10(m, 2H), 2.39-2.45(m, 1H), 2.75(t, J=11.5Hz, 0.3H), 3.11(dd, J=5.7, 13.4Hz, 0.7H), 3.7 9 (s, 2, 1H), 3.81 (s, 0.9H), 4.00-4.06 (m, 0.7H), 4.58-4.67 (m, 0.3H), 4.62 (m, 0.3H), 5.20 (d, J=5.9 Hz, 0.7H); MS m/z: 256 (M+H) ⁺ .

Stage 4

(2S,5R)-methyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate hydrochloride (10)

A solution of (2S,5S)-methyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (32.71 g, 0.128 mol) in anhydrous acetonitrile (250 ml) was cooled to -30°C followed by the addition of 2,6-lutidine (16.9 ml) and the addition of trifluoromethanesulfonic anhydride (22.5 ml) at a temperature of -36 to -30°C for 15 minutes. After stirring at -32° C. for 25 minutes, benzyloxyamine (32.25 g) was added dropwise at -32° C. or lower, then washed with acetonitrile (10 ml). After gradually warming the reaction mixture to 0° C., 2,6-lutidine (16.9 ml) was added and stirred at 4° C. for 2 days. The reaction mixture was concentrated to 150 ml, then diluted with ethyl acetate (750 ml) and washed with water (750 ml), 10% aqueous citric acid solution (3×750 ml), saturated aqueous sodium bicarbonate solution (375 ml) and brine (400 ml). Each aqueous layer was re-extracted with ethyl acetate (400 ml), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give 46.93 g of a residue. 38.24 g of the obtained residue is taken and diluted with ethyl acetate (120 ml). At room temperature, 1M hydrogen chloride-ethyl acetate 160 ml (0.160 mol) is added to crystallize and hexane (560 ml) is added. After stirring at 0° C. for 3 hours, the crystals are filtered, washed with hexane (400 ml) and then dried in vacuo to give 30.36 g of the title compound as a crystalline powder (73% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ was obtained as a mixture of two rotamers. 2.00-2.09 (m, 3H), 2.23-2.24 (m, 1H), 3.33-3.42 (m, 0.5H), 3.74 (dd, J=3.2, 15.6 Hz, 0.5H), 3.79 (s, 2H), 3.81 (s, 1H), 3.89 (brs, 1H), 4 .29 (d, J=15.9 Hz, 0.5H), 4.81 (d, J=14.4 Hz, 0.5H), 5.08-5.16 (m, 2.5H); MS m/z: 361 (M-HCl+H) ⁺ .

Stage 5

(2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate dihydrochloride (4b)

To (2S,5R)-methyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate hydrochloride (1.951 g, 4.92 mmol) was added 2M hydrogen chloride-methanol (40 ml), then refluxed for 3 days. Then the reaction solution was concentrated to 14 ml, and ethyl acetate (40 ml) was added to precipitate crystals. The suspension was stirred at room temperature for 1.5 hours, then filtered through a Kiriyama funnel, washed with ethyl acetate (80 ml) and dried in vacuo to give 1.439 g of the title compound as a crystalline powder (87% yield). The measurement data for this product is the same as for Example 12.

Example 115

(2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylate dihydrochloride (4b); Synthesis from commercially available (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (7)

Stage 1

(2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate hydrochloride (8)

Commercially available (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (84% content, net 912.22 g, washed with 2M hydrogen chloride-methanol 3.1 L) was added to 2M hydrogen chloride-methanol (12.8 L) and the mixture was refluxed for 3 hours (internal temperature 63-67°C). The reaction mixture is cooled, 1,4-dioxane (12.8 L) is added and the solvent is evaporated off under reduced pressure. Ethyl acetate (18.3 L) and ice-cold 44% aqueous potassium carbonate solution (23.7 L) were added to the residue (4.1 kg), then the organic layer was separated. The aqueous layer was then extracted with ethyl acetate (3 x 18.3 L). A 50% potassium carbonate aqueous solution (7.3 L) was separated in each organic layer, the organic layers were combined, dried over anhydrous potassium carbonate (2.37 kg) and filtered, and the solvent was distilled off under reduced pressure. The residue was dissolved in toluene (9.1 L) and activated charcoal (9.2 g) was added, then stirred for 30 minutes, filtered and the solvent was distilled off under reduced pressure. The residue was replaced with ethyl acetate (9.1 L) and concentrated to give 1130 g of the title compound as a pale yellow oil (78.9% content, 891.57 g net, 89% yield).

Stage 2

(2S,5S)-Methyl-5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (9)

A solution of (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate (content 78.8%, net 459.48 g) in anhydrous ethyl acetate (7.4 L) was cooled to -40° C. and triethylamine (1300 g) was added dropwise followed by trifluoroacetic acid anhydride (1349 g) washed with anhydrous ethyl acetate (1 00 ml) at -40 to -12°C for 30 minutes. The temperature was raised to -2°C over 15 minutes after the completion of the dropwise addition, then stirred for 75 minutes. Then water (1277 ml) was added to the mixture, stirred at 25° C. for 1 hour. The mixture was added to water (8.4 L) (washed with ethyl acetate 4.5 L), then extracted with ethyl acetate (2×9.8 L). The combined organic layers were washed successively with 1M hydrochloric acid (8.5 L), saturated aqueous sodium bicarbonate (8.5 L) and brine (8.5 L), then dried over anhydrous sodium sulfate (1.8 kg) and filtered. After the solvent of the organic layer was evaporated under reduced pressure, ethyl acetate (3.6 L) was added to the residue, then displaced and concentrated. The residue was dried in vacuo to give 793.4 g of the title compound (content 81.5%, net 648.66 g, yield 88).

Stage 3

(2S,5R)-Methyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (10)

A solution of (2S,5S)-methyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (content 81.5%, net 556.23 g) in anhydrous acetonitrile (4.0 L) was cooled to -40°C, 2,6-lutidine (259.24 g) was added (washed with acetonitrile (100 ml) and trifluoromethanesulfonic acid anhydride (645.72 g) was added dropwise at -43 to -37°C for 1 hour and 10 minutes (washed with acetonitrile 100 ml) Then the reaction mixture was stirred at -35°C for 50 minutes, benzyloxyamine (550.27 g) was added dropwise at -35°C or less, then washed with The reaction mixture was then gradually warmed to -5° C., 2,6-lutidine (259.24 g) was added, stirred at 5° C. for 40 hours. The mixture was concentrated to 1.8 L, then diluted with ethyl acetate (12.4 L) and washed with water (12.4 L), 10% aqueous citric acid solution (4×8 L + 4.7 L), saturated aqueous sodium bicarbonate solution (6.3 L) and brine (7.2 L) Dry the organic layer over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue was dried in vacuo to give 867.73 g of the title compound (71.56% content, 79% yield).

Stage 4

(2S,5R)-methyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate hydrochloride (10)

(2S,5R)-Methyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (content 70.13%, net 673.20 g) was diluted with ethyl acetate (4.8 L) and activated charcoal (48 g) was added, stirred for 1 hour. The mixture is filtered and washed with ethyl acetate (2 L). The filtrate was diluted with ethyl acetate (4.7 L) and 1M hydrogen chloride-ethyl acetate solution (2.7 L) was added at room temperature, then stirred for 15 minutes. Then add hexane 28.6 l, and the mixture is cooled to 0°C. After stirring and maturing for 3 hours, the crystals are filtered off, washed with hexane/ethyl acetate=4/1 (3 L) and then dried in vacuo to give the title compound (content 91.72%, yield 90%).

Stage 5

(2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate dihydrochloride (4b)

(2S,5R)-Methyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (content 92.01%, net 732.25 g) was dissolved in 2M hydrogen chloride-methanol solution (15 L), refluxed for 27 hours. The mixture is cooled to room temperature and concentrated to 3 L under reduced pressure. Methanol (2.7 L) was added to the mixture, followed by ethyl acetate (16.3 L) and the mixture was stirred for 1 hour. The precipitated crystals are filtered, washed with ethyl acetate (3 x 1.1 L) and dried in vacuo to give 572.0 g of the title compound (98.06% content, 92% yield). The measurement data for this product is the same as for Example 12.

Example 116

(2S,5R)-5-((Benzyloxy)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (IV-a3)

(2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate dihydrochloride (4b) described in Example 12 (6.64 g, 20 mmol) was dissolved in water (40 ml) and 1,4-dioxane (27 ml) was added, then cooled with ice. A 5M aqueous sodium hydroxide solution (13.2 ml) was added, followed by stirring for 1 hour. To the reaction mixture were added 5M hydrochloric acid (1.2 ml), potassium carbonate (2.76 g), di-tert-butoxycarbonyl dicarbonate (4.8 g), then warmed to room temperature and stirred overnight. The aqueous solution obtained after concentration of the reaction mixture was washed with ether, then adjusted to pH 3.3 by adding citric acid monohydrate, extracted twice with ethyl acetate (50 ml), washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. 6.87 g of the title compound are obtained (quantitative). The measurement data for this product is the same as for example 99.

Example 117

Obtaining the enzyme β-lactamase

Using the genome of Pseudomonas aeruginosa ATCCBAA-47, plasmid pBR322, Klebsiella pneumoniae ATCCBAA-1705, and P. aeruginosa MSC17696 as a template, each DNA for encoding β-lactamase, AmpC, TEM-1, CRC-2, or OXA-2 domain, except for the signal peptide, was expanded by PCR. Each of the PCR products was introduced into the pET-28b(+)vector (Merck), introduced into Escherichia coli BL21(DE3) (Merck) and after induction with 1 mM isopropyl-β-D-(-)-thiogalactopyranoside (Nacalai Tesque), cultured overnight at 20°C to express AmpC, TEM-1, CRS-2 or OXA-2. After bacterial cell harvest, AmpC is purified from sonicated cell extract using CM Sepharose Fast Flow (GE Healthcare) and HiTrap Heparin HP (GE Healthcare) at 4°C. TEM-1 clear HiTrap SPHP (GE Healthcare), HiTrap Q (GE Healthcare) and Mono Q (GE Healthcare), and KPC-2 clear HiTrap SPHP. OXA-2 is purified by HiTrap SPHP and HiTrap Heparin HP.

Example 118

Inhibition of β-lactamase

To measure β-lactamase inhibitory activity, 100 μM (final concentration) nitrocephin (Oxoid) was used as a substrate, and 2.5% DMSO, 10 μg/ml bovine serum albumin (Sigma-Aldrich) and 50 mM phosphate buffer at pH 7 was used as a reaction solution. Test compounds, tazobactam (TAZ, LKT Laboratories), NXL104 (prepared by patent document method 1, 99.5% purity, Meiji Seika Pharma Co., Ltd.) or MK-7655 (prepared by patent document method, 99.4% purity, Meiji Seika Pharma Co., Ltd.) and AmpC, TEM-1, K are added to each well of a 96-well plate. PC-2 or OXA-2 (final concentrations of 0.5 nM, 0.1 nM, 0.5 nM or 2 nM, respectively), then pre-incubated at 30° C. for 10 minutes. Nitrocefin is added to each for mixing, then incubated at 30° C. for 20 minutes, Multiscan Ascent (Thermo Fisher Scientific) is used to measure the wavelength of 492 nm, thereby measuring the hydrolytic activity of nitrocephin against β-lactamase, to determine the inhibitory effect on the enzyme. As a control, a reaction solution containing no β-lactamase is prepared, and the concentration of the test compound showing 50% inhibition is determined as the IC ₅₀ value. As the inhibition strength, values less than 0.1 μM, less than 1 μM, less than 3 μM, less than 10 μM, and 10 μM or more are shown with A, B, C, D, and E, respectively. The results are shown in Table 5.

Class A β-lactamase: KPC-2, TEM-1

Class C β-lactamase: AmpC

Class D β-lactamase: OXA-2 (ESBL)

Table 5 Inhibitory action against β-lactamase Compound AmpC TEM-1 KRS-2 OKHA-2 TAZ IN A IN A NXL104 IN A IN IN MK-7655 IN A IN IN Example 17 IN A IN D Example 18 IN A IN WITH Example 19 IN A IN NT Example 20 IN IN WITH D Example 21 IN A IN C Example 22 IN A IN D Example 23 IN A IN D Example 24 IN IN IN NT Example 25 IN A A E Example 26 WITH IN WITH NT Example 27 IN A WITH WITH Example 28 A A IN D Example 29 IN A V D Example 30 IN A V NT Example 31 IN A IN D Example 32 A A IN D Example 33 IN A V D Example 34 A A V D Example 35 IN A D WITH Example 36 IN A WITH D Example 37 WITH A WITH WITH Example 38 V A IN WITH Example 39 A A WITH WITH Example 40 IN A D WITH Example 41 V IN WITH D Example 42 V IN IN WITH Example 43 V A IN WITH Example 44 A A A WITH Example 45 A A IN WITH Example 46 A A IN WITH Example 47 IN A V D Example 48 A IN V D Example 49 IN A V D Example 50 A IN V D Example 5 1 IN A V WITH Example 52 IN A V WITH Example 53 IN A V NT Example 54 A A V IN Example 55 IN IN With D Example 56 V A V WITH Example 57 V A With NT Example 58 A A A IN Example 59 IN A V WITH Example 60 V A V V Example 61 V A With With Example 62 V A V With Example 63 V A V With Example 64 V A V With Example 65 V IN With With Example 66 IN A WITH WITH Example 67 IN A WITH WITH Example 68 A A IN With Example 69 IN A With V Example 70 IN A V V Example 71 IN A V NT Example 72 A A V IN Example 73 A A V NT Example 74 A A V IN Example 75 IN A V With Example 76 IN A V V Example 77 IN A V V Example 78 V A With With Example 79 V A With With Example 80 V A With V Example 81 A A V With Example 82 A A V V Example 83 A A V V Example 84 A A With V Example 85 A A V V Example 86 A A V NT Example 87 A A A V Example 88 IN A V V Example 89 A A A V Example 90 A A IN V Example 91 A A A V Example 92 A A IN V Example 93 A A IN V Example 94 A A V V Example 95 A A A With Example 96 A A IN With Example 97 A A A V NT: not tested; A: <0.1 µM, B: <1 µM, C: <3 µM, D: <10 µM, E: ≥10 µM

119 Example

Synergistic effect

The synergistic effect of a test compound with a β-lactam agent against bacteria was evaluated using a constitutively expressing AmpC strain, P. aeruginosa ATCCBAA-47CR, selected from ATCCBAA-47 through exposure to the agent, a KPC-2 producing strain, K. pneumonia ATCCBAA-1705, and a CTX-M-15 (ESBL) and OXA-1 producing strain, E. coli MSC 19503. Using piperacillin (PIPC, Sigma-Aldrich) as the β-lactam agent, the minimum inhibitory concentration (MIC) of PIPC was measured by the agar plate dilution method of the Institute of Clinical and Laboratory Standards (ICLS method). That is, an agar plate containing PIPC at each concentration is adjusted in the usual ratio of 2 dilution series in Mueller-Hinton agar (MHA, Becton, Dickinson and Company) to give a test compound having 1/4 or 1/8 of the corresponding concentration of PIPC, and the bacteria are cultured overnight in cation-adjusted Mueller-Hinton broth (CAMHB, Becton, Dickinson and Company) are adjusted in the same medium to give 10 ⁴ cfu/site and seeded onto a plate containing the agent. The plate is cultured overnight at 35° C. and the minimum concentration of agent found at which there is no bacterial growth is determined as the MIC. Antibacterial activity of PIPC alone against AmpC constitutively expressing P. aeruginosa, KPC-2 producing K. pneumonia and CTX-M-15 (ESBL) and OXA-1 producing E. coli is shown at 64 μg/mL, >128 μg/mL, >128 μg/mL, respectively, and values at which PIPC antibacterial action is noted that are less than 1/1 6, less than 1/4 and less than 1/1, and not restored by the synergistic action of the test compounds, shown with A, B, C and D, respectively. The results are shown in Table 6.

Class A β-lactamase: KPC-2, CTX-M-15 (ESBL)

Class C β-lactamase: AmpC

Class D β-lactamase: OXA-1

Table 6 organism P. aeruginosa K. pneumoniae E. coli bacterial strain ATCCBAA-47CR ATCCBAA-1705 MSC19503 Producing enzyme AmpC(++) KPC-2 CTX-M-15, OXA-1 Compound Compound/PIPC ratio Improvement action TAZ 1/8 D D IN NXL104 1/8 IN IN A Example 17 1/8 IN IN A Example 18 1/4 D WITH IN Example 19 1/4 WITH IN A Example 20 1/4 WITH IN A Example 21 1/8 WITH A A Example 22 1/8 WITH A A Example 23 1/8 WITH IN A Example 24 1/8 WITH WITH IN Example 25 1/4 WITH IN A Example 26 NT NT NT NT Example 27 1/8 WITH A A Example 28 1/8 WITH A A Example 29 1/8 WITH IN A Example 30 1/4 D WITH IN Example 31 1/8 WITH IN A Example 32 1/4 WITH IN A Example 33 NT NT NT NT Example 34 1/8 WITH IN A Example 35 1/8 IN A A Example 36 1/8 WITH A A Example 37 1/8 WITH IN A Example 38 1/8 WITH A A Example 39 1/8 WITH IN A Example 40 1/8 WITH IN A Example 41 1/8 WITH A A Example 42 1/8 WITH IN A Example 43 1/8 WITH IN A Example 44 1/8 WITH IN IN Example 45 1/8 WITH IN A Example 46 1/8 WITH IN A Example 47 1/8 WITH IN IN Example 48 1/8 WITH WITH IN Example 49 1/4 D IN A Example 50 1/8 WITH IN A Example 51 1/8 WITH IN A Example 52 1/8 WITH IN A Example 53 1/4 WITH WITH IN Example 54 1/8 WITH IN A Example 55 NT NT NT NT Example 56 1/8 WITH IN A Example 57 1/4 WITH IN A Example 58 1/8 WITH WITH A Example 59 1/8 IN IN A Example 60 1/8 D WITH IN Example 61 1/8 IN A A Example 62 1/8 WITH IN A Example 63 1/8 WITH IN A Example 64 1/8 WITH A A Example 65 1/8 WITH A A Example 66 1/8 IN IN A Example 67 1/8 IN A A Example 68 1/8 IN IN IN Example 69 1/8 IN IN A Example 70 1/8 WITH IN A Example 71 1/8 D WITH IN Example 72 1/8 WITH IN A Example 73 1/8 WITH IN A Example 74 1/8 WITH IN A Example 75 1/8 IN A A Example 76 1/8 WITH A A Example 77 1/8 IN A A Example 78 1/8 WITH A A Example 79 1/8 IN IN A Example 80 1/8 WITH IN A Example 81 1/8 IN IN IN Example 82 1/8 IN IN A Example 83 1/8 WITH IN A Example 84 1/8 IN IN A Example 85 1/8 IN IN A Example 86 1/8 WITH IN A Example 87 1/8 WITH IN A Example 88 1/8 D IN A Example 89 1/8 WITH IN A Example 90 1/8 WITH IN A Example 91 1/8 WITH IN A Example 92 1/8 IN IN A Example 93 1/8 WITH IN A Example 94 1/8 D WITH A Example 95 1/8 WITH IN A Example 96 1/8 WITH IN A Example 97 1/8 WITH IN A NT: not tested; A: <1/16, B: <1/4, C: <1, D: ≥1

Example 120

The synergistic effect of the test compounds synthesized in examples 59, 61 and 69 with a β-lactam agent against bacteria was evaluated using KPC-2 producing the K. pneumoniae strain ATCCBAA-1705, CTX-M-15 (ESBL) and OXA-1 producing the strain E. coli MSC19503 and AmpC constitutively expressing the P. aeruginosa strain ATC CBAA-47CR. Ampicillin (ABPC, Sigma-Aldrich), amoxicillin (AMPC, Sigma-Aldrich), piperacillin (PIPC), ceftazidime (CAZ, Sigma-Aldrich), cefepime (CFPM, United States Pharmacopeial Convention), cefotaxime (CTX, Sigma-Aldrich), ceftriaxone (CTRX, Sigma-Aldrich), imipenem (IPM, United States Pharma) copeial convention), biapenem (BIPM, Meiji Seika Pharma), meropenem (MEPM, United States Pharmacopeial Convention), doripenem (DRPM, Sequoia Research Products), cefminox (CMNX, Meiji Seika Pharma), flomoxef (FMOX, Shionogi & Co, Ltd), aztreonam (AZT, United States Pharmacopeial Convention) as a β-lactam agent. The MIC of each β-lactam agent is measured by a broth microdilution method based on the CLSI method. That is, a liquid medium containing 4 μg/ml (final concentration) of the test compound, TAZ, NXL104 or MK-7655 and β-lactam agent and the test compound at each concentration is adjusted to a total ratio of 2 dilution series in CAMHB, and the bacteria are cultured overnight in CAMHB, adjusted in the same medium so as to obtain 10 ⁵ cfu/ml and inoculated into liquid and environment containing the agent. This liquid medium containing the agent is cultured overnight at 35° C. and the minimum concentration of the agent at which there is no bacterial growth is determined as the MIC. The results are shown in tables 7-9.

Table 7 Synergistic MIC (µg/mL) Organism, bacterial strain (producing enzyme) Antibiotic Separately Example 59 Example 61 Example 69 TAZ NXL104 MK-7655 P. aeruginosa PAO1CR (AmpC) ABPC >64 64 >64 >64 >64 >64 >64 AMPC >64 64 64 64 >64 >64 64 PIPC >64 4 4 4 >64 8 8 CAZ 64 2 2 2 32 2 2 CFPM 16 2 2 2 16 2 2 CTX >64 16 16 16 >64 64 16 CTRX >64 16 16 8 >64 32 16 IPM 1 0.25 0.5 0.5 1 0.25 0.25 BIPM 0.5 0.25 0.25 0.25 0.5 0.25 0.25 MEPM 1 0.5 0.5 1 1 0.5 0.5 DRPM 1 0.25 0.5 0.5 1 0.25 0.25 CMNX >64 >64 >64 >64 >64 >64 >64 FMOX >64 >64 >64 >64 >64 >64 >64 AZT 32 4 4 8 32 8 4

Table 8 Synergistic MIC (mcg/mL) Organism, bacterial strain (producing enzyme) Antibiotic Separately Example 59 Example 61 Example 69 TAZ NXL104 MK-7655 K. pneumoniae MSC19408(KPC-2) ABPC >64 ≤0.031 ≤0.031 ≤0.031 >64 16 64 AMPC >64 ≤0.031 ≤0.031 ≤0.031 >64 32 >64 PIPC >64 ≤0.031 ≤0.031 ≤0.031 >64 8 32 CAZ >64 ≤0.031 ≤0.031 ≤0.031 >64 0.5 2 CFPM >64 ≤0.031 ≤0.031 ≤0.031 >64 ≤0.031 0.25 STX >64 ≤0.031 ≤0.031 ≤0.031 >64 0.063 0.5 CTRX >64 ≤0.031 ≤0.031 ≤0.031 >64 0.063 0.5 IPM 8 ≤0.031 ≤0.031 ≤0.031 4 0.125 0.063 BIPM 16 ≤0.031 ≤0.031 ≤0.031 8 0.125 0.063 MEPM 16 ≤0.031 ≤0.031 ≤0.031 4 ≤0.031 ≤0.031 DRPM 8 ≤0.031 ≤0.031 ≤0.031 4 ≤0.031 ≤0.031 CMNX 16 ≤0.031 ≤0.031 ≤0.031 16 0.25 2 FMOX >64 ≤0.031 ≤0.031 ≤0.031 32 0.063 0.5 AZT >64 ≤0.031 ≤0.031 ≤0.031 >64 0.063 0.5

Table 9 Synergistic MIC (mcg/mL) Organism, bacterial strain (producing enzyme) Antibiotic Separately Example 59 Example 61 Example 69 TAZ NXL104 MK-7655 E. coli MSC19503 (CTX-M-15, OXA-1) ABPC >64 ≤0.031 ≤0.031 ≤0.031 >64 4 >64 AMPC >64 ≤0.031 ≤0.031 ≤0.031 >64 4 >64 PIPC >64 ≤0.031 ≤0.031 ≤0.031 >64 4 >64 CAZ >64 ≤0.031 ≤0.031 ≤0.031 0.5 0.25 1 CFPM >64 ≤0.031 ≤0.031 ≤0.031 0.25 ≤0.031 0.125 STX >64 ≤0.031 ≤0.031 ≤0.031 0.25 ≤0.031 1 CTRX >64 ≤0.031 ≤0.031 ≤0.031 0.25 ≤0.031 1 IPM 0.25 ≤0.031 ≤0.031 ≤0.031 0.125 0.25 0.25 BIPM 0.25 ≤0.031 ≤0.031 ≤0.031 0.125 0.25 0.25 MEPM <0.031 ≤0.031 ≤0.031 ≤0.031 ≤0.031 ≤0.031 ≤0.031 DRPM <0.031 ≤0.031 ≤0.031 ≤0.031 ≤0.031 ≤0.031 ≤0.031 CMNX 1 ≤0.031 ≤0.031 ≤0.031 1 0.125 0.5 FMOX 0.25 ≤0.031 ≤0.031 ≤0.031 0.25 <0.031 0.125 AZT >64 ≤0.031 ≤0.031 ≤0.031 0.25 0.063 0.5

Example 121

The synergistic effect of the test compounds synthesized in Examples 59, 61 and 69 with a β-lactam agent against bacteria was evaluated using 5 strains from each of KPC-2 or 3 producing strains, K. pneumonia, AmpC constitutively expressing strain, P. aeruginosa, AmpC constitutively expressing strain, Enterobacteriaceae, metallo-β-lactamase producing strain type IMP, Enterobacteriaceae, CTX -M-15 (ESBL) producing strain of E. coli. Using PIPC as the β-lactam agent, the MIC of the β-lactam agent is measured by the agar plate dilution method based on the CLSI method. That is, an agar plate containing 4 µg/mL (final concentration) of test compound, TAZ, NXL104 or MK-7655 and β-lactam agent and test compound at each concentration is adjusted to a total ratio of 2 dilution series in MHA, and the bacteria are cultured overnight in CAMHB, adjusted in the same medium so as to obtain 10 ⁴ CFU/mL and inoculated onto the plate containing the agent . This tablet containing the agent is cultured overnight at 35° C. and the minimum concentration of the agent at which there is no bacterial growth is determined as the MIC. The results are shown in Figures 1-5.

Example 122

Measurement of activity against tuberculous bacilli

The combined effect of the compound of Example 59 with a β-lactam agent against TB bacillus was evaluated using clinical isolates of multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB), and susceptible TB (H37Rv). Using meropenem (MEPM), biapenem (MBPM), tebipenem (TBPM, Meiji Seika Pharma), ampicillin (ABPC), amoxicillin (AMPC) as a β-lactam agent, the MIC of each β-lactam agent was measured by a liquid medium dilution method based on the BrothMIC MTB-I method (Kyokuto Pharmaceutical Industrial Co., Ltd.). That is, a liquid medium is prepared containing 4 μg/mL (final concentration) of the compound of Example 50 and the β-lactam agent at each concentration adjusted for a total ratio of 2 dilution series in Middlebrook 7H9 liquid medium (Becton, Dichkinson and Company) containing 5% bovine serum albumin, 2% dextrose, 0.005% bovine liver catalase, and 0.05% Tween-80 and a bacterial suspension adjusted to OD ₆₆₀ =0.16-0.2 are inoculated at a 200-fold dilution. The medium is cultured for 7 days at 37°C under humidified conditions, and the minimum concentration of the agent at which there is no growth of bacteria is determined as the MIC.

As a result, the antibacterial activity (µg/mL) of a single β-lactam agent against MDR-TB, XDR-TB and H37Rv is 16, 4 and 1 for MEPM, 16, 2 and 1 for BIPM, 4, 1 and 0.5 for TBPM, 128, 32 and 16 for ABPC and 128, 64 and 16 for AMPC, and antibacterial activity when used in combination with Example 59 is 8, 1 and 0.5 for MEPM, 4, 1 and 1 for BIPM, 2, 0.5 and 0.25 for TBPM, 32, 16 and 2 for ABPC and 64, 16 and 26 for AMPC.

Claims (149)

1. A diazabicyclooctane derivative represented by the following formula (I): , in the above formula (I) A is Ra(Rb)N- or RcO-; B is NH; C is benzyl, H or SO ₃ M, where M is pyridinium or tetrabutylammonium; Ra and Rb are each, independently of each other, H, methyl, benzoyl, C _1-4 alkylcarbonyl, heterocyclylcarbonyl, where heterocyclyl is selected from tetrahydropyran, piperidine and pyrrolidine, and heteroarylcarbonyl, where heteroaryl is selected from furan, oxazole and pyridine; Rc is C _1-3 alkyl or 4-6 membered heterocyclyl having one nitrogen atom selected from azetidine, pyrrolidine and piperidine; A can be modified with 0 to 3 Fn1 substituents, where the Fn1 substituent that can modify A can be further modified with Fn1; Fn1 is C _1-6 alkyl, which is selected from cyclopropylmethyl and cyclobutyl, O= or Rg-(CH ₂ ) _0-1 -, where Rg is a 4-7 membered heterocyclyl containing 1-2 heteroatoms selected from a nitrogen atom and an oxygen atom selected from azetidine, pyrrolidine, piperidine, morpholine, imizolidine, piperazine and diazepan, phenyl, a 5-membered heteroaryl having 1-2 nitrogen atoms selected from pyrrole and imidazole, RdO ₂ S-, Re(Rf)N-, Re(Rf)NCO-, ReO-, ReOCO- or a protective group, where Rd is methyl; Re and Rf are each independently H or C _1-4 alkyl, and additionally Ra and Rb can be closed by linkage to give a 5-6 membered heterocyclyl having at least one nitrogen atom or nitrogen and an oxygen atom which is selected from pyrrolidine and morpholine, Rc and B can be closed by linkage to give a 5-6 membered heterocyclyl having a nitrogen atom and an oxygen atom which is selected from oxazolidine and oxazinane, and Re and Rf can be closed by linkage to give a morpho lina, the protecting group is selected from tert-butoxycarbonyl, benzyloxycarbonyl and triisopropylsilyl, or a pharmaceutically acceptable salt thereof. 2. The diazabicyclooctane derivative represented by the following formula (II): , in the above formula (II) Rc is C _1-3 alkyl or 4-6 membered heterocyclyl having one nitrogen atom selected from azetidine, pyrrolidine and piperidine; B is NH; C is benzyl, H or SO ₃ M, where M is pyridinium or tetrabutylammonium; Rc can be modified with 0 to 3 Fn1 substituents, where the Fn1 substituent, which can modify Rc, can be further modified with Fn1; Fn1 is cyclobutyl, O= or Rg, where Rg is a 4-7 membered heterocyclyl having 1-2 heteroatoms selected from a nitrogen atom and an oxygen atom selected from azetidine, pyrrolidine, piperidine, morpholine, imizolidine, piperazine and diazepan, a 5-membered heteroaryl having 1-2 nitrogen atoms selected from pyrrole and imidazole, RdO ₂ S-, Re(Rf )N-, ReO-, ReOCO- or a protective group, where Rd is methyl; Re and Rf are each independently H or C _1-4 alkyl, and additionally Rc and B can be closed by bonding to give a 5-6 membered heterocyclyl having a nitrogen atom and an oxygen atom, which is selected from oxazolidine and oxazinane, the protecting group is selected from t-butoxycarbonyl, benzyloxycarbonyl and triisopropylsilyl or a pharmaceutically acceptable salt thereof. 3. The diazabicyclooctane derivative represented by the following formula (IIa): , in the above formula (IIa) OBn is benzyloxy and Rc and B are the same as defined for the compound of claim 2, or a pharmaceutically acceptable salt thereof. 4. A diazabicyclooctane derivative represented by the following formula (IIb): , in the formula (IIb) above, Rc and B are the same as those defined for the compound according to claim 2, its pharmaceutically acceptable salt. 5. The diazabicyclooctane derivative represented by the following formula (III): , in the above formula (III) Rc, B and M are the same as defined for the compound according to claim 2, or a pharmaceutically acceptable salt thereof. 6. The compound according to any one of claims 1 to 5, which is represented by the following formulas: in the formulas above, P ² is t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or H; when P ² is H, P ³ is benzyl (Bn), H, or SO ₃ M, where M is pyridinium or tetrabutylammonium, and when P ² is t-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz), P ³ is benzyl (Bn), H, or SO ₃ M; where M is pyridinium or tetrabutylammonium, or a pharmaceutically acceptable salt thereof. 7. The method for obtaining the compound according to claim 5, represented by the following formula (III): , in the above formula (III) Rc, B and M have the same meanings as defined for the compound according to claim 2, which is included in paragraph 2, including a combination of a compound represented by the following formula (IV-a): , in the above formula (IV-a), P ¹ is a protective group that can be removed with an acid, a base, or a nucleophilic agent; and OBn is benzyloxy, with an RcOBH compound using an active ester, an active amide, or a dehydrating condensing agent to obtain a compound represented by the following formula (IV-b): , in the above formula (IV-b), P ¹ is a protective group that can be removed with an acid, a base, or a nucleophilic agent; Rc and B are as defined for the compound of claim 2, and OBn is benzyloxy, deprotection of P ¹ , which is a protecting group, to obtain a compound represented by the following formula (IV-c): , in the above formula (IV-c), Rc and B have the meanings defined for the compound according to claim 2, and OBn is benzyloxy, silylation of a compound in a reaction system, followed by subjecting an intramolecular urea formation reaction to obtain a compound represented by the following formula (IIa): in the above formula (IIa), Rc and B have the meanings defined for the compound according to claim 2, and OBn is benzyloxy, then removal of the benzyl from the benzyloxy at position 6 using a hydrogenolysis catalyst under hydrogen atmosphere to obtain a compound represented by the following formula (IIb): , in the above formula (IIb) Rc and B have the meanings defined for the compound according to claim 2, and sulfonation of the hydroxyl group at position 6 in the presence of a base and, if necessary, deprotection of the side chain: RcOB-. 8. The method for obtaining the compound according to claim 3, represented by the following formula (IIa): , in the above formula (IIa), Rc and B have the meanings defined for the compound according to claim 2, and OBn is benzyloxy, which is included in clause 2, including a combination of a compound represented by the following formula (IV-a): in the above formula (IV-a), P ¹ is a protective group that can be removed with an acid, a base or a nucleophilic agent; and OBn is benzyloxy, with an RcOBH compound using an active ester, an active amide, or a dehydrating condensing agent to obtain a compound represented by the following formula (IV-b): , in the above formula (IV-b), P ¹ is a protective group that can be removed with an acid, a base, or a nucleophilic agent; Rc and B are as defined for the compound of claim 2, and OBn is benzyloxy, deprotection of P ¹ , which is a protecting group, to obtain a compound represented by the following formula (IV-c): , in the above formula (IV-c), Rc and B have the meanings defined for the compound according to claim 2, and OBn is benzyloxy, silylation of the compound in the reaction system, followed by the reaction of the formation of intramolecular urea. 9. The method for obtaining the compound according to claim 3, represented by the following formula (IIa): , in the above formula (IIa), Rc and B have the meanings defined for the compound according to claim 2, and OBn is benzyloxy, which is included in clause 2, including silylation of a compound represented by the following formula (IV-c): , in the above formula (IV-c), Rc and B have the meanings defined for the compound according to claim 2, and OBn is benzyloxy, in the reaction system, followed by the reaction of the formation of intramolecular urea. 10. A method for producing a compound represented by the following formula (III): , in the above formula (III) Rc, B and M have the meanings defined for the compound according to claim 2, which is included in clause 2, including removal of benzyl from benzyloxy at the 6-position of the compound represented by the following formula (IIa): , in the above formula (IIa), Rc and B have the meanings defined for the compound according to claim 2, and OBn is benzyloxy, using a hydrogenolysis catalyst under a hydrogen atmosphere to obtain a compound represented by the following formula (IIb): , in the above formula (IIb) Rc and B have the meanings defined for the compound according to claim 2, and sulfonation of the hydroxyl group at position 6 in the presence of a base and, if necessary, deprotection of the side chain: RcOB-. 11. A method for producing a compound represented by the following formula (III-Boc-059): , in the above formula (III-Boc-059), Boc is t-butoxycarbonyl and M is pyridinium or tetrabutylammonium, including among the compounds represented by the following formulas (IV-a2), (IV-a3) and (IV-a4): in the above formula (IV-a2), (IV-a3) or (IV-a4) TFA is trifluoroacetyl, Boc is t-butoxycarbonyl, Teos is 2-trimethylsilylethoxycarbonyl and OBn is benzyloxy, a combination of a compound represented by formula (IV-a2) or (IV-a4) with tert-butyl 2-(aminooxy)ethyl carbamate using an active ester, an active amide or a dehydrating condensing agent, or combining a compound represented by formula (IV-a3) with benzyl 2-(aminooxy)ethyl carbamate using an active ester, an active amide or a dehydrating condensing agent, to obtain a compound represented by the following formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or (IV-b4-Boc-059): , in the above formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or (IV-b4-Boc-059) TFA is trifluoroacetyl, Boc is t-butoxycarbonyl, Cbz is benzyloxycarbonyl, Teos is 2-trimethylsilylethoxycarbonyl and OBn is benzyloxy, deprotection of the trifluoroacetyl compound represented by the formula (IV-b2-Boc-059) by treatment with a base to obtain a compound represented by the following formula (IV-c-Boc-059): , in the above formula (IV-c-Boc-059) or (IV-c-Cbz-059) Boc is t-butoxycarbonyl, Cbz is benzyloxycarbonyl and OBn is benzyloxy, removing tert-butoxycarbonyl of a compound represented by formula (IV-b3-Cbz-059) by treatment with acid to obtain a compound represented by the following formula (IV-c-Cbz-059), or removing 2-trimethylsilylethoxycarbonyl of a compound represented by formula (IV-b4-Boc-059) with fluoride to obtain a compound represented by the following formula (IV-c-Boc-059), then, after silylation of the above compound (IV-c-Boc-059) or (IV-c-Cbz-059) in the reaction system, an intramolecular urea formation reaction to obtain a compound represented by the following formula (IIa-Boc-059) or (IIa-Cbz-059): , in the above formula (IIa-Boc-059) or (IIa-Cbz-059) Boc is t-butoxycarbonyl, Cbz is benzyloxycarbonyl and OBn is benzyloxy, removing benzyl from the benzyloxy at the 6-position of a compound represented by formula (IIa-Boc-059) using a hydrogenolysis catalyst under hydrogen atmosphere, or removing the benzyl from the benzyloxy at the 6-position of the compound represented by formula (IIa-Cbz-059) using a hydrogenolysis catalyst under hydrogen atmosphere and simultaneously tert-butoxycarbonylating it in the presence of di-tert-butoxydicarbonate to give the compound represented by the following formula (IIb-Boc-059): , in the above formula (IIb-Boc-059), Boc is t-butoxycarbonyl, sulfonation of the hydroxyl group at position 6. 12. A method for obtaining a compound represented by the following formula (III-Boc-059): , in the above formula (III-Boc-059) Boc is t-butoxycarbonyl and M is pyridinium or tetrabutylammonium, including among the compounds represented by the following formulas (IIa-Boc-059) and (IIa-Cbz-059): , in the above formulas (IIa-Boc-059) and (IIa-Cbz-059) Boc is t-butoxycarbonyl, Cbz is benzyloxycarbonyl, and OBn is benzyloxy, removing benzyl from the benzyloxy at the 6-position of a compound represented by formula (IIa-Boc-059) using palladium on carbon under a hydrogen atmosphere, or removal of benzyl from the benzyloxy at the 6-position of the compound represented by formula (IIa-Cbz-059) using palladium on carbon under hydrogen atmosphere in the presence of di-tert-butoxydicarbonate, and simultaneous tert-butoxycarbonylation to give the compound represented by formula (IIb-Boc-059): , in the above formula (IIb-Boc-059), Boc is t-butoxycarbonyl, sulfonation of the hydroxyl group at position 6 using a sulfur trioxide-pyridine complex in the presence of pyridine, 2-picoline or 2,6-lutidine. 13. A method for obtaining a compound represented by the following formula (III-Boc-059): , in the above formula (III-Boc-059) Boc is t-butoxycarbonyl and M is pyridinium or tetrabutylammonium, including removal of benzyl from benzyloxy at position 6 of the compound represented by the formula (IIa-Boc-059): , in the above formula (IIa-Boc-059) Boc is t-butoxycarbonyl and OBn is benzyloxy, using palladium-on-charcoal under a hydrogen atmosphere to obtain a compound represented by the formula (IIb-Boc-059): , in the above formula (IIb-Boc-059), Boc is t-butoxycarbonyl, sulfation of the hydroxyl group at position 6 using a sulfur trioxide-pyridine complex in the presence of pyridine, 2-picoline or 2,6-lutidine.

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