Process for boron-containing compounds

Abstract

Described herein are methods for boron-containing compounds, specifically boron-containing compounds, compositions, and methods of their preparation.

Description

[0001] This application is a divisional application of Chinese patent application No. 202180080510.2, filed on August 5, 2021, entitled "Method for Using Boron-Containing Compounds" (the corresponding PCT application was filed on August 5, 2021, with application number PCT / US2021 / 044808).

[0002] Cross-Reference This application claims the benefit of U.S. Provisional Application Serial No. 63 / 088,872, filed on October 7, 2020, which is incorporated herein by reference in its entirety.

[0003] Statement Regarding Federally Sponsored Research This invention was developed by the National Institutes of Health / National Institute of Allergy and Infectious Diseases with the support of the U.S. government, under contract number HHSN27220160029C. The government holds certain rights to this invention. Background Technology

[0004] This invention relates to boron-containing compounds and methods for their preparation. The compounds and pharmaceutical compositions comprising them can be used as inhibitors of β-lactamases and as antibacterial agents. Summary of the Invention

[0005] This article discloses a method for preparing compounds of formula (III): The method in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be independently hydrogen, fluorine, or chlorine; The method includes using a compound of formula (II): It reacts with oxidizing agents.

[0006] In some embodiments, the oxidant is potassium permanganate (KMnO4). In some embodiments, the method further includes an alkali.

[0007] In some implementations, the method includes: (i) The compound of formula (II): Suspended in water; (ii) Add a base to dissolve the compound of formula (II) in water; (iii) Add the oxidant while stirring; (iv) Stir; (v) Add solvent to deactivate excess oxidant; (vi) To stir; (vii) Filter to obtain filtrate; (viii) Acidify the filtrate to obtain a slurry; (viii) Cooling the slurry; and (ix) Filter the slurry to obtain compound (III): .

[0008] In some embodiments, the base in step (ii) is sodium hydroxide. In some embodiments, the oxidant is potassium permanganate (KMnO4). In some embodiments, step (iii) is performed for about 10 hours to about 20 hours. In some embodiments, step (iii) is performed for about 16 hours. In some embodiments, the temperature in step (iii) is maintained between about 20°C and about 30°C. In some embodiments, the solvent that deactivates the excess oxidant is a primary or secondary alcohol solvent. In some embodiments, the solvent that deactivates the excess oxidant is ethanol. In some embodiments, step (vi) is performed for about 10 minutes to about 2 hours. In some embodiments, step (vi) is performed for about 30 minutes. In some embodiments, prior to acidification, the filtrate obtained in step (vii) is cooled in step (viii) to between about 0°C and about 10°C. In some embodiments, prior to acidification, the filtrate is cooled in step (viii) to about 5°C. In some embodiments, the acid used for acidification is sulfuric acid. In some embodiments, the compound of formula (III) is obtained by filtration.

[0009] In some embodiments, the compound of formula (II) is: It is achieved by making compound (I): The compound is obtained by reacting with a lithium reagent, followed by a reaction with a borate ester. In some embodiments, the compound of formula (I) is contacted with a lithium reagent to form the compound of formula (Ia): In some embodiments, the compound of formula (Ia) is not isolated. In some embodiments, the compound of formula (Ia) is further reacted with the borate ester to form the compound of formula (II). In some embodiments, the lithium reagent is n-BuLi. In some embodiments, the borate ester is B(OiPr)3.

[0010] In some implementations, the method includes: (i) Compounds of formula (I): Combined with diamine in solvent; (ii) Stirring; (iii) Add lithium reagent; (iv) Stir; (v) Add borate ester; (vi) Quenching the reaction by adding an acidic aqueous solution; (vii) Separate the layers to obtain the organic layer; (viii) Add an alkaline aqueous solution to the organic layer; (ix) Separate the layers to obtain the water layer; (x) Add acid to the aqueous layer; (xi) Cooling to obtain a suspension; (xii) To stir; (xiii) Filter the suspension to obtain the compound of formula (II): .

[0011] In some embodiments, the diamine is TMEDA. In some embodiments, the solvent used in step (i) is cyclohexane. In some embodiments, the lithium reagent is nBuLi.

[0012] In some embodiments, the borate ester is B(OiPr)3. In some embodiments, the addition of the lithium reagent in step (iii) is carried out over about 1 hour to about 6 hours. In some embodiments, the addition of the lithium reagent in step (iii) is carried out while maintaining a temperature between about 0°C and about 20°C. In some embodiments, step (iv) is carried out over about 2 hours to about 3 hours. In some embodiments, the temperature is cooled to below -70°C prior to the addition of the borate ester in step (v). In some embodiments, the temperature is raised to above -20°C after the addition of the borate ester in step (v). In some embodiments, the acidic aqueous solution in step (vi) is an HCl solution. In some embodiments, the alkaline aqueous solution in step (viii) is a NaOH solution. In some embodiments, the cooling temperature in step (xi) is about 0°C and about 5°C.

[0013] In some embodiments, the method further includes making the compound of formula (III): It reacts with (1S,2S,3R,5S)-(+)-pinenediol in a solvent to form compound (IV): In some embodiments, the solvent is n-heptane.

[0014] In some implementations, the method includes: (i) The compound of formula (III), (1S,2S,3R,5S)-(+)-pinenediol are mixed with the solvent; (ii) The mixture obtained by heating; (iii) Cooling to obtain a slurry; (iv) Filtration to obtain the compound of formula (IV).

[0015] In some embodiments, the solvent is n-heptane. In some embodiments, the heating is performed to achieve reflux. In some embodiments, step (ii) further includes removing water. In some embodiments, the cooling temperature in step (iii) is below about 60°C.

[0016] This article also discloses a method for preparing compound (A): A method using a compound of formula (III) prepared by any one of claims 1 to 17: ; in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be hydrogen, fluorine, or chlorine independently.

[0017] In some embodiments, the compound of formula (III): It reacts with (1S,2S,3R,5S)-(+)-pinenediol to form compound (IV): In some embodiments, the compound of formula (IV) is: It reacts with the carboxyl protecting group to form a compound of formula (V): , where P 2 It is a carboxyl protecting group. In some embodiments, the carboxyl protecting agent is SOCl2, followed by NaOtBu.

[0018] In some embodiments, the compound of formula (V) is: It reacts with chloroiodomethane and a sterically hindered Grignard reagent to form a compound of formula (VI): In some embodiments, the sterically hindered Grignard reagent is isopropyl magnesium chloride, cyclohexyl magnesium chloride, or isopropyl magnesium chloride:lithium chloride. In some embodiments, the sterically hindered Grignard reagent is isopropyl magnesium chloride:lithium chloride. In some embodiments, the compound of formula (VI): The compound reacts with dichloromethane and a base, followed by a Lewis acid, to give compound (VII): In some embodiments, the base is lithium diisopropylamino or 2,2,6,6-tetramethylpiperidinylmagnesium chloride:lithium chloride. In some embodiments, the base is lithium diisopropylamino.

[0019] In some embodiments, the Lewis acid is ZnCl2. In some embodiments, the compound of formula (VII) is: It reacts with a protected ammonium reagent to form a compound of formula (VIII): , where P 3 and P 4 It is an amine protecting group. In some embodiments, the protected ammonium reagent is a metal salt of hexaalkyldisilazane. In some embodiments, the compound of formula (VIII): and The reaction forms a compound of formula (IX): In some embodiments, the method further includes a coupling agent.

[0020] In some embodiments, the coupling agent is HATU, EDC, HBTU, HCTU, HOBt, PyAOP, PyBOP, or TBTU. In some embodiments, the coupling agent is HATU. In some embodiments, the compound of formula (IX): It reacts with acid to form a compound of formula (A): Or its pharmaceutically acceptable salt.

[0021] This article also discloses a method for preparing compound (B): A method using a compound of formula (III) prepared by any one of claims 1 to 17: ; in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be hydrogen, fluorine, or chlorine independently.

[0022] In some embodiments, the compound of formula (III): It reacts with (1S,2S,3R,5S)-(+)-pinenediol to form compound (IV): In some embodiments, the compound of formula (IV) is: It reacts with a carboxyl protecting agent to form a compound of formula (V): , where P 2 It is a carboxyl protecting group. In some embodiments, the carboxyl protecting agent is SOCl2, followed by NaOtBu. In some embodiments, the compound of formula (V): It reacts with chloroiodomethane and a sterically hindered Grignard reagent to form a compound of formula (VI): In some embodiments, the sterically hindered Grignard reagent is isopropyl magnesium chloride, cyclohexyl magnesium chloride, or isopropyl magnesium chloride:lithium chloride. In some embodiments, the sterically hindered Grignard reagent is isopropyl magnesium chloride:lithium chloride. In some embodiments, the compound of formula (VI): The compound reacts with dichloromethane and a base, followed by a Lewis acid, to give compound (VII): In some embodiments, the base is lithium diisopropylamino or 2,2,6,6-tetramethylpiperidinylmagnesium chloride:lithium chloride. In some embodiments, the base is lithium diisopropylamino. In some embodiments, the Lewis acid is ZnCl2. In some embodiments, the compound of formula (VII): It reacts with a protected ammonium reagent to form a compound of formula (VIII): , where P 3 and P 4 It is an amine protecting group. In some embodiments, the protected ammonium reagent is a metal salt of hexaalkyldisilazane. In some embodiments, the compound of formula (VIII): It reacts with EtC(=O)Cl to form a compound of formula (X): In some embodiments, the compound of formula (X) is: It reacts with a deprotecting agent to form a compound of formula (XI): In some embodiments, the deprotecting agent is methanesulfonic acid. In some embodiments, the compound of formula (XI): and The reaction forms a compound of formula (XII): In some embodiments, the compound of formula (XII) is: In the presence of alkali metal salts or quaternary ammonium salts of bromine or iodine, it reacts with propionyl chloride to form compound (B): In some embodiments, the alkali metal salt of bromine is LiBr. In some embodiments, the compound of formula (B) is made as follows: With R 1 The -OH reaction forms a compound of formula (C): , where R 1It is optionally substituted C1 to C6 alkyl, optionally substituted C1 to C6 haloalkyl, optionally substituted C1 to C6 hydroxyalkyl, optionally substituted C1 to C6 aminoalkyl, optionally substituted C1 to C6 deuteralkyl, optionally substituted C1 to C6 heteroalkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C1 to C6 alkyl)cycloalkyl, optionally substituted (C1 to C6 alkyl)heterocycloalkyl, optionally substituted (C1 to C6 alkyl)aryl, or optionally substituted (C1 to C6 alkyl)heteroaryl.

[0023] In some implementation schemes, P 1 It is a C1 to C6 alkyl group. In some embodiments, P 1 It is methyl. In some embodiments, R a R b and R c It can be either hydrogen or fluorine independently. In some implementations, R a R b and R c It is hydrogen. In some implementations, R a It is a halogen. In some implementations, R b It is a halogen. In some implementations, R c It is a halogen. In some implementations, P 2 It is a C1 to C6 alkyl group. In some embodiments, P 2 It is tert-butyl. In some implementations, P 3 and P 4 It is trimethylsilyl. In some embodiments, R 1 It is an optionally substituted C1 to C6 alkyl, an optionally substituted C1 to C6 haloalkyl, or an optionally substituted C1 to C6 deuteralkyl. In some embodiments, R 1 It is an optionally substituted C1 to C6 alkyl group. In some embodiments, R 1 It is a C1 to C6 alkyl group. In some embodiments, R 1 It is ethyl. In some embodiments, the compound of formula (A) is Or its pharmaceutically acceptable salt. In some embodiments, the compound of formula (B) is In some embodiments, the compound of formula (C) is .

[0024] Incorporation by Reference All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application specifically and individually indicates by reference to be incorporated by reference. Detailed Implementation

[0025] Antibiotics are the most effective drugs for the clinical treatment of bacterial infections. They are widely used due to their good antibacterial effects and limited side effects. Among them, β-lactam antibiotics (such as penicillins, cephalosporins, and carbapenems) are widely used because of their strong bactericidal effects and low toxicity.

[0026] To counteract the efficacy of various β-lactam antibiotics, bacteria have evolved to produce inactivating enzymes called β-lactamases, which act on β-lactam substrates. These β-lactamases are classified as either "serine" or "metal," based on the presence of key serine or zinc residues at the enzyme's active site, respectively. The rapid spread of this bacterial resistance mechanism can severely limit β-lactam treatment options in hospitals and communities. To combat this type of resistant bacteria, β-lactamase inhibitors have been developed, which, when used in combination with other antibiotics, restore the effectiveness of β-lactams. Therefore, the discovery of new β-lactamase inhibitors has become a key focus in the discovery and development of new antimicrobial therapies.

[0027] Large-scale production of clinically useful drug candidates typically requires good manufacturing practices. This article provides specific processes and methods for preparing novel β-lactamase inhibitors or intermediates for their synthesis.

[0028] definition As used in the specification and appended claims, unless otherwise specified, the following terms shall have the following meanings.

[0029] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly specifies otherwise.

[0030] When this document uses the term "scope" to refer to physical properties, such as molecular mass, or chemical properties, such as chemical formulas, it means to include the scope of all combinations and sub-combinations, as well as the specific implementations thereof.

[0031] When referring to a number or range of values, the term “approximately” means that the number or range of values ​​referred to is an approximation within the range of experimental variability (or within the range of statistical experimental error), and therefore the number or range of values ​​varies between 1% and 15% of the number or range of values.

[0032] The term “comprising” (and related terms such as “including” or “having” or “containing”) does not imply exclusion from other specific embodiments, such as any composition of substances, composition, method or method etc. described herein, which are “composed of” or “substantially composed of” the features described.

[0033] As used herein, the terms “treatment” or “curing,” “relief” or “improvement” may be used interchangeably. These terms refer to methods of achieving beneficial or desired outcomes, including but not limited to therapeutic benefits and / or preventative benefits. A “therapeutic benefit” means the eradication or improvement of an underlying condition that is being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying condition, resulting in an improvement observed in a patient, even though the patient still has the underlying condition. For preventative benefits, the composition is administered to a patient at risk of developing a specific disease, or to a patient reporting one or more physical symptoms of a disease, even if the disease has been diagnosed.

[0034] As used herein, "room temperature" means 25 ± 5°C. In some embodiments, the room temperature is 20°C. In some embodiments, the room temperature is 21°C. In some embodiments, the room temperature is 22°C. In some embodiments, the room temperature is 23°C. In some embodiments, the room temperature is 24°C. In some embodiments, the room temperature is 25°C. In some embodiments, the room temperature is 26°C. In some embodiments, the room temperature is 27°C. In some embodiments, the room temperature is 28°C. In some embodiments, the room temperature is 29°C. In some embodiments, the room temperature is 30°C.

[0035] "alkyl" means a straight-chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms or 1 to 6 carbon atoms with optional substitutions, or a branched saturated hydrocarbon monoradical with optional substitutions, wherein the sp3 hybrid carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever the numerical range appears herein, such as "C1 to C6 alkyl" means that the alkyl group consists of 1, 2, 3, 4, 5, or 6 carbon atoms; however, this definition also covers the occurrence of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C1 to C6. 10Alkyl, C1 to C9 alkyl, C1 to C8 alkyl, C1 to C7 alkyl, C1 to C6 alkyl, C1 to C5 alkyl, C1 to C4 alkyl, C1 to C3 alkyl, C1 to C2 alkyl, or C1 alkyl. Unless otherwise specified in the specification, the alkyl group is optionally substituted with groups described below, such as oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl group is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.

[0036] "Alkoxy" refers to the formula -OR a free radicals, of which R a As defined, it is an alkyl radical. Unless otherwise specified in the specification, the alkoxy group may be optionally substituted with groups described below, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.

[0037] "Alkenyl" refers to an optionally substituted straight-chain hydrocarbon monoradical or an optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either a cis or trans conformation with respect to the double bond and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears herein, numerical ranges such as "C2 to C6 alkenyl" mean that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms; however, this definition also covers the occurrence of the term "alkenyl" where no numerical range is specified. In some embodiments, the alkenyl is C2 to C6. 10The alkenyl group can be C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, or C2. Unless otherwise expressly stated in the specification, the alkenyl group may be optionally substituted, for example, with an oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group may be optionally substituted with an oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group may be optionally substituted with an oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl group may be optionally substituted with a halogen.

[0038] "Alynyl" refers to a single radical of an optionally substituted straight-chain hydrocarbon or a single radical of an optionally substituted branched hydrocarbon, having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, acetylenyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears herein, numerical ranges such as "C2 to C6 alkynyl" mean that the alkynyl group may consist of 2, 3, 4, 5, or 6 carbon atoms; however, this definition also covers the occurrence of the term "alkynyl" where no numerical range is specified. In some embodiments, the alkynyl group is C2 to C6. 10 The alkynyl group can be C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, or C2. Unless otherwise expressly stated in the specification, the alkynyl group is optionally substituted, for example, with an oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted with an oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted with an oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with a halogen.

[0039] "Deuterated alkyl" refers to an alkyl radical, as defined above, substituted with one or more deuterium atoms. In some embodiments, the alkyl group is substituted with one deuterium atom. In some embodiments, the alkyl group is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuterium atoms. Deuterated alkyl groups include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterated alkyl group is CD3.

[0040] "Halogenated alkyl" refers to an alkyl radical, as defined above, that is substituted with one or more halogen atoms. In some embodiments, the alkyl group is substituted with one, two, or three halogen atoms. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six halogens. Halogenated alkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. In some embodiments, the alkyl group is trifluoromethyl.

[0041] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1 to C6 heteroalkyl group, wherein the heteroalkyl group consists of one to six carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof), wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, or -CH(CH3)OCH3. Unless otherwise specifically stated in the specification, the heteroalkyl group may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with a halogen.

[0042] "Hydroxyalkyl" refers to an alkyl radical, as defined above, which is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0043] "Aminoalkyl" refers to an alkyl radical, as defined above, which is substituted with one or more amino groups. In some embodiments, the alkyl group is substituted with one amino group. In some embodiments, the alkyl group is substituted with one, two, or three amino groups. Hydroxyalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl group is aminomethyl.

[0044] "Aryl" refers to a free radical derived from a hydrocarbon ring system, comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. Aryl free radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the aryl group is bonded through aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group. Aryl groups include, but are not limited to, aryl groups derived from hydrocarbon ring systems of anthracene, naphthylene, phenanthrene, anthracene, azulene, benzene, phenanthrene, fluorene, as-dicyclopentadienzobenzene, s-dicyclopentadienzobenzene, indene, indene, naphthalene, propylenenaphthalene, phenanthrene, heptane, pyrene, and triphenylene. In some embodiments, the aryl group is a phenyl group. Unless otherwise specified in the specification, the aryl group may be optionally substituted with groups described below, for example, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the aryl group is optionally substituted with halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, -OMe groups, NH2 groups, or -NO2 groups. In some embodiments, the aryl group is optionally substituted with halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups.

[0045] "Cycloalkyl" refers to a stable, partially or fully saturated, monocyclic or polycyclic carbon ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl group is bonded through non-aromatic atoms) or bridged ring systems. Representative cycloalkyl groups include, but are not limited to, those having three to fifteen carbon atoms (C3 to C4). 15 cycloalkyl groups, ranging from three to ten carbon atoms (C3 to C4). 10Cycloalkyl groups are cyclic alkyl groups consisting of three to eight carbon atoms (C3 to C8 cycloalkyl), three to six carbon atoms (C3 to C6 cycloalkyl), three to five carbon atoms (C3 to C5 cycloalkyl), or three to four carbon atoms (C3 to C4 cycloalkyl). In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocyclic compounds include, for example, adamantyl, norbornel, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl compounds include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly stated in the specification, cycloalkyl groups are optionally substituted with groups described below, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0046] "Halogen" or "halogen" refers to a bromine group, a chlorine group, a fluorine group, or an iodine group. In some embodiments, the halogen is a fluorine group or a chlorine group. In some embodiments, the halogen is a fluorine group.

[0047] "Halogenated alkyl" refers to an alkyl group as defined above that is substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0048] "Heterocyclic alkyl" refers to a stable 3- to 24-membered partial or fully saturated cyclic group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. Unless otherwise expressly stated in the specification, heterocyclic alkyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic cyclic systems, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl is bonded through non-aryl ring atoms) or bridged cyclic systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic alkyl radical may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heterocyclic alkyl is a 3- to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl is a 5- to 6-membered heterocyclic alkyl. Examples of such heterocyclic alkyl radicals include, but are not limited to, azirropropyl, azirrobutyl, oxacyclobutyl, dioxacyclopentane, thienyl[1,3]dithiohexane, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidyl, oxazolyl, piperidinyl, piperazine, 4-piperidinoneyl, pyridinyl Heteroalkyl, pyrazolyl, quinoyl, thiazoyl, tetrahydrofuranyl, trithiohexacyclohexyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxacyclopenten-4-yl, and 2-oxo-1,3-dioxacyclopenten-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise stated, heterocycloalkyl has from 2 to 10 carbon atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is different from the total number of atoms (including heteroatoms) constituting the heterocycloalkyl group (i.e., the skeleton atoms of the heterocycloalkyl ring). Unless otherwise specified in the specification, heterocyclic alkyl groups are optionally substituted with groups described below, for example, substituted with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc. In some embodiments, heterocyclic alkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocyclic alkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.

[0049] "Heteroaryl" refers to a 5- to 14-membered ring system group comprising one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. Heteroaryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl group is bonded through aromatic ring atoms) or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl radical may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. Examples include, but are not limited to, azaheptatrienyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzo-m-dioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptatrienyl, 1,4-benzodioxane, benzonaphthuryl, benzooxazolyl, benzo-m-dioxacyclopentenyl, benzodioxacyclohexadienyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenyl, dibenzofuranyl, dibenzothienyl, furanyl, furanone , isothiazolyl, imidazolyl, indazole, indoleyl, indazole, isoindoleyl, indolinyl, isoindolinyl, isoquinolinyl, indoleazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxozadicyclic heptatrienyl, oxazolyl, oxadicyclopropane, 1-oxonionic pyridinyl, 1-oxonionic pyrimidinyl, 1-oxonionic pyrazinyl, 1-oxonionic pyridazinyl 1-Phenylacetyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purine, pyrrolyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified in the specification, heteroaryl groups are optionally substituted with groups described below, for example, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, heteroaryl groups are optionally substituted with halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the heteroaryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe.

[0050] Methods for the preparation of organoboron compounds In some embodiments, the raw materials and reagents used to synthesize the compounds described herein are synthetic or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fisher Scientific (Fisher Chemical), and AcrosOrganics.

[0051] In further embodiments, the compounds described herein and other related compounds with different substituents are synthesized using techniques and materials described herein and those recognized in the art, such as those in, for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry, 4th Edition (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry, 4th Edition, Volumes A and B (Plenum 2000, 2001); and Green and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (Wiley). (All of these are incorporated herein by reference in 1999)

[0052] The compounds described in WO / 2014 / 089365, WO / 2014 / 110442, WO / 2014 / 515958, and WO / 2015 / 1191907 have been proven to be effective β-lactamase inhibitors. Continued drug development of these compounds requires readily available large quantities of pure material. Many common synthetic intermediates for these β-lactamase inhibitors are compounds of formula (IV): , where P 1 It is a hydroxyl protecting group; and R a R b and R c It can be hydrogen, fluorine, or chlorine independently. In some embodiments, the compound of formula (IV) is compound 4: .

[0053] Compound 4 was previously prepared using the synthetic route described in Scheme 1. The starting material 3-iodo-2-methoxybenzoic acid was converted to compound 4 by using bis-((+)-pinanediol)-diboron and a palladium catalyst. Option 1 A better synthetic route for compound 4 is needed. Few suppliers provide the starting material 3-iodo-2-methoxybenzoic acid on a large scale, and 3-iodo-2-methoxybenzoic acid is typically prepared using environmentally unfriendly chemical methods involving electrophilic aromatic halogenation and nitration. Furthermore, these synthetic routes involve the use of potentially genotoxic reagents and intermediates such as sodium nitrite, nitroaromatics, and aniline, and may also generate N-nitrosoaromatic impurities. The use of such chemicals requires specialized analytical methods and controls to meet stringent safety limits. In addition, bisboron reagents are expensive, commercially available only from a limited number of manufacturers, and only about half of the reagent is incorporated into the product.

[0054] Improved methods This document discloses an improved method for preparing formula (IV) compounds, as shown in Scheme 2 below. In some embodiments, the improved method has fewer steps than the previously described method. Option 2 This article discloses compounds of formula (I): Preparative (IV) compounds: The method.

[0055] This article discloses an improved method for preparing compound 4, as shown in Scheme 3 below. Option 3 This article discloses the method for extracting compound 1: Preparation of compound 4: The method used is that compound 1 is readily available commercially.

[0056] This document discloses applications for compounds of formula (I): Compound (II) is prepared by reacting with a lithium reagent, followed by a reaction with a borate ester: The method.

[0057] In some embodiments of the method for preparing compounds of formula (II), a compound of formula (I) is contacted with a lithium reagent to form a compound of formula (Ia): .

[0058] In some embodiments of the method for preparing compound (II), compound (Ia) is not isolated.

[0059] In some embodiments of the method for preparing compound (II), compound (Ia) is further reacted with a borate ester to form compound (II).

[0060] In some embodiments of the method for preparing compound (II), the lithium reagent is n-BuLi. In some embodiments of the method for preparing compound (II), the lithium reagent is n-hexyllithium.

[0061] In some embodiments of the method for preparing compounds of formula (II), the borate ester is B(OiPr)3.

[0062] In some embodiments of the method for preparing compounds of formula (II), the method includes: (i) Compounds of formula (I): Combined with diamine in solvent; (ii) Stirring; (iii) Add lithium reagent; (iv) Stir; (v) Add borate ester; (vi) Quenching the reaction by adding an acidic aqueous solution; (vii) Separate the layers to obtain the organic layer; (viii) Add an alkaline aqueous solution to the organic layer; (ix) Separate layers to obtain a water layer; (x) Add acid to the aqueous layer; (xi) Cooling to obtain a suspension; (xii) To stir; (xiii) Filter the suspension to obtain compound (II): .

[0063] In some embodiments of the method for preparing compounds of formula (II), the diamine is TMEDA.

[0064] In some embodiments of the method for preparing compound (II), the solvent used in step (i) is cyclohexane.

[0065] In some embodiments of the method for preparing compound (II), the lithium reagent is nBuLi. In some embodiments of the method for preparing compound (II), the lithium reagent is n-hexyllithium.

[0066] In some embodiments of the method for preparing compounds of formula (II), the borate ester is B(OiPr)3.

[0067] In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 1 hour to approximately 10 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 3 hours to approximately 10 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 5 hours to approximately 10 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 1 hour to approximately 9 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 3 hours to approximately 9 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 5 hours to approximately 9 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 1 hour to approximately 8 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 3 hours to approximately 8 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 5 hours to approximately 8 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 1 hour to approximately 7 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 3 hours to approximately 7 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 5 hours to approximately 7 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 1 hour to approximately 6 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 3 hours to approximately 6 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 1 hour to approximately 5 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed over approximately 3 hours to approximately 5 hours. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is carried out over a period of about 1 hour to about 4 hours.In some embodiments of the method for preparing compound (II), step (iv) is carried out for about 2 to about 3 hours.

[0068] In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed while the temperature is maintained between about 0°C and about 20°C. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed while the temperature is maintained between about 0°C and about 30°C. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed while the temperature is maintained between about 10°C and about 20°C. In some embodiments of the method for preparing compound (II), the addition of the lithium reagent in step (iii) is performed while the temperature is maintained between about 10°C and about 30°C.

[0069] In some embodiments of the method for preparing compound (II), the temperature is cooled to below -70°C before the boronic ester is added in step (v). In some embodiments of the method for preparing compound (II), the temperature is cooled to -75°C before the boronic ester is added in step (v).

[0070] In some embodiments of the method for preparing compound (II), after adding the borate ester in step (v), the temperature is raised to above -20°C.

[0071] In some embodiments of the method for preparing compound (II), the acidic aqueous solution in step (vi) is an HCl solution.

[0072] In some embodiments of the method for preparing compound (II), the alkaline aqueous solution in step (viii) is a NaOH solution.

[0073] In some embodiments of the method for preparing compound (II), the cooling temperature in step (xi) is about 0°C and about 5°C. In some embodiments of the method for preparing compound (II), the cooling temperature in step (xi) is about 0°C and about 10°C. In some embodiments of the method for preparing compound (II), the cooling temperature in step (xi) is about 5°C and about 10°C.

[0074] In some embodiments of the method for preparing compound (II), the acidic aqueous solution in step (x) is an HCl solution.

[0075] In some embodiments of the method for preparing compound (II), compound (II) is obtained by filtration: In some embodiments of the method for preparing compound (II), the obtained filter cake is washed with water.

[0076] In some embodiments of the method for preparing compounds of formula (II), P 1 It is a C1 to C6 alkyl group. In some embodiments of the method for preparing compounds of formula (II), P 1 It is a methyl group.

[0077] In some embodiments of the method for preparing compounds of formula (II), R a R b and R c Independently, it is either hydrogen or fluorine. In some embodiments of the method for preparing compounds of formula (II), R a It is a halogen. In some embodiments of the method for preparing compounds of formula (II), R b It is a halogen. In some embodiments of the method for preparing compounds of formula (II), R c It is a halogen. In some embodiments of the method for preparing compounds of formula (II), R a R b and R c It is halogen.

[0078] This article describes a method for preparing compounds of formula (III): Methods; in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be independently hydrogen, fluorine, or chlorine; The method includes using a compound of formula (II): It reacts with oxidizing agents.

[0079] In some embodiments of the method for preparing compound (III), the oxidizing agent is potassium permanganate (KMnO4). In some embodiments of the method for preparing compound (III), the oxidizing agent is a chromium reagent. In some embodiments of the method for preparing compound (III), the oxidizing agent is a copper reagent.

[0080] In some embodiments of the method for preparing compounds of formula (III), the method further includes a base.

[0081] In some embodiments of the method for preparing compounds of formula (III), the method includes: (i) Compound of formula (II): Suspended in water; (ii) Add a base to dissolve the compound of formula (II) in water; (iii) Add the oxidant while stirring; (iv) Stir; (iv) Add solvent to deactivate excess oxidant; (v) To stir; (vi) Filter to obtain filtrate; (vii) Acidify the filtrate to obtain a slurry; (viii) Cooling slurry; and (ix) Filter the slurry to obtain compound (III): .

[0082] In some embodiments of the method for preparing compounds of formula (III), the base in step (ii) is sodium hydroxide.

[0083] In some embodiments of the method for preparing compounds of formula (III), the oxidant is potassium permanganate (KMnO4). In some embodiments of the method for preparing compounds of formula (III), the oxidant is a chromium reagent.

[0084] In some embodiments of the method for preparing compound (III), step (iii) is performed for about 10 hours to about 20 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for about 15 hours to about 20 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for about 10 hours to about 15 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for about 15 hours to about 18 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for about 10 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for about 11 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for about 12 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for about 13 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for about 14 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for about 15 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for approximately 16 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for approximately 17 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for approximately 18 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for approximately 19 hours. In some embodiments of the method for preparing compound (III), step (iii) is performed for approximately 20 hours.

[0085] In some embodiments of the method for preparing compound (III), the oxidant is added in batches. In some embodiments of the method for preparing compound (III), the oxidant is added in batches to maintain the temperature between about 20°C and about 30°C.

[0086] In some embodiments of the method for preparing compound (III), the temperature is maintained between about 20°C and about 30°C in step (iii). In some embodiments of the method for preparing compound (III), the temperature is maintained at less than or equal to 35°C in step (iii).

[0087] In some embodiments of the method for preparing compound (iv), step (iv) is performed for about 1 hour to about 20 hours. In some embodiments of the method for preparing compound (iv), step (iv) is performed for about 1 hour to about 10 hours. In some embodiments of the method for preparing compound (iv), step (iv) is performed for about 1 hour to about 5 hours. In some embodiments of the method for preparing compound (iv), step (iv) is performed for about 5 hours to about 10 hours. In some embodiments of the method for preparing compound (iv), step (iv) is performed for about 5 hours to about 8 hours.

[0088] In some embodiments of the method for preparing compounds of formula (III), the solvent for deactivating the excess oxidant is a primary alcohol solvent or a secondary alcohol solvent. In some embodiments of the method for preparing compounds of formula (III), the solvent for deactivating the excess oxidant is ethanol.

[0089] In some embodiments of the method for preparing compound (III), step (vi) is performed for about 10 minutes to about 2 hours. In some embodiments of the method for preparing compound (III), step (vi) is performed for about 30 minutes. In some embodiments of the method for preparing compound (III), step (vi) is performed for about 1 hour. In some embodiments of the method for preparing compound (III), step (vi) is performed for about 2 hours.

[0090] In a method for preparing compounds of formula (III), the filtrate obtained in step (vii) is cooled in step (viii) to between about 0°C and about 10°C before acidification.

[0091] In some embodiments of the method for preparing compounds of formula (III), the filtrate is cooled to about 5°C in step (viii) prior to acidification.

[0092] In some embodiments of the method for preparing compounds of formula (III), the acid used for acidification is sulfuric acid.

[0093] In some embodiments of the method for preparing compounds of formula (III), compounds of formula (III) are obtained by filtration.

[0094] In some embodiments of the method for preparing compounds of formula (III), P 1 It is a C1 to C6 alkyl group. In some embodiments of the method for preparing compounds of formula (III), P 1 It is a methyl group.

[0095] In some embodiments of the method for preparing compounds of formula (III), R aR b and R c Independently, it is either hydrogen or fluorine. In some embodiments of the method for preparing compounds of formula (III), R a It is a halogen. In some embodiments of the method for preparing compounds of formula (III), R b It is a halogen. In some embodiments of the method for preparing compounds of formula (III), R c It is a halogen. In some embodiments of the method for preparing compounds of formula (III), R a R b and R c It is hydrogen.

[0096] This article describes a compound of formula (III): Preparative (IV) compounds: The method.

[0097] In some embodiments of the method for preparing compounds of formula (IV), compounds of formula (III) are made: It reacts with (1S,2S,3R,5S)-(+)-pinenediol in a solvent to form compound (IV): .

[0098] In some embodiments of the method for preparing compound (IV), the solvent is n-heptane.

[0099] In some embodiments of the method for preparing formula (IV) compounds, the method includes: (i) Mix the compound of formula (III), (1S,2S,3R,5S)-(+)-pinenediol with a solvent; (ii) The mixture obtained by heating; (iii) Cooling to obtain a slurry; (iv) Filtration to obtain compound of formula (IV).

[0100] In some embodiments of the method for preparing compound (IV), the solvent is n-heptane.

[0101] In some embodiments of the method for preparing (IV) compounds, heating is performed to achieve reflux.

[0102] In some embodiments of the method for preparing compound (IV), step (ii) further includes removing water.

[0103] In some embodiments of the method for preparing compound (IV), the cooling temperature in step (iii) is below about 60°C.

[0104] In some embodiments of the method for preparing formula (IV) compounds, P 1 It is a C1 to C6 alkyl group. In some embodiments of the method for preparing formula (IV) compounds, P 1 It is methyl. In some embodiments of the method for preparing formula (IV) compounds, R a R b and R c Independently, it is either hydrogen or fluorine. In some embodiments of the method for preparing formula (IV) compounds, R a It is a halogen. In some embodiments of the method for preparing formula (IV) compounds, R b It is a halogen. In some embodiments of the method for preparing formula (IV) compounds, R c It is a halogen. In some embodiments of the method for preparing formula (IV) compounds, R a R b and R c It is hydrogen.

[0105] This document discloses a method for preparing compounds of formula (A), as outlined in Scheme 4: Option 4 This article discloses a method for preparing compound (A): The method uses a compound of formula (III) prepared by the method disclosed herein: ; in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be hydrogen, fluorine, or chlorine independently.

[0106] In some embodiments of the method for preparing compound (A), compound (III) is made: It reacts with (1S,2S,3R,5S)-(+)-pinenediol to form compound (IV): .

[0107] As disclosed herein, one method for preparing compound (A) is as follows: The method uses a compound of formula (IV) prepared by the method disclosed herein: ; in: P 1 It is a hydroxyl protecting group; and R a R band R c It can be hydrogen, fluorine, or chlorine independently.

[0108] In some embodiments of the method for preparing compound (A), compound (IV) is made: It reacts with the carboxyl protecting group to form a compound of formula (V): , where P 2 It is a carboxyl-protected group.

[0109] In some embodiments of the method for preparing compound (A), the carboxyl protecting agent is SOCl2, followed by NaOtBu.

[0110] In some embodiments of the method for preparing compound (A), compound (V) is made as follows: It reacts with chloroiodomethane and a sterically hindered Grignard reagent to form a compound of formula (VI): .

[0111] In some embodiments of the method for preparing compound (A), the sterically hindered Grignard reagent is isopropyl magnesium chloride, cyclohexyl magnesium chloride, or isopropyl magnesium chloride:lithium chloride.

[0112] In some embodiments of the method for preparing compound (A), compound (VI) is made: The compound reacts with dichloromethane and a base, followed by a Lewis acid, to give compound (VII): .

[0113] In some embodiments of the method for preparing compound (A), the base is diisopropylaminolithium or 2,2,6,6-tetramethylpiperidinylmagnesium chloride:lithium chloride. In some embodiments of the method for preparing compound (A), the base is diisopropylaminolithium.

[0114] In some embodiments of the method for preparing compound (A), the Lewis acid is ZnCl2.

[0115] In some embodiments of the method for preparing compound (A), compound (VII) is made: It reacts with a protected ammonium reagent to form a compound of formula (VIII): , where P 3 and P 4 It is an amine protecting group.

[0116] In some embodiments of the method for preparing compound (A), the protected ammonium reagent is a metal salt of hexaalkyldisilazane.

[0117] In some embodiments of the method for preparing compound (A), compound (VIII) is made: and The reaction forms a compound of formula (IX): .

[0118] In some embodiments of the method for preparing compound (A), the method further includes a coupling agent. In some embodiments of the method for preparing compound (A), the coupling agent is HATU, EDC, HBTU, HCTU, HOBt, PyAOP, PyBOP, or TBTU. In some embodiments of the method for preparing compound (A), the coupling agent is HATU.

[0119] In some embodiments of the method for preparing compound (A), compound (IX) is made: It reacts with acid to form a compound of formula (A): Or its pharmaceutically acceptable salt.

[0120] In some embodiments of the method for preparing compound (A), P 1 It is a C1 to C6 alkyl group. In some embodiments of the method for preparing compound (A), P 1 It is a methyl group.

[0121] In some embodiments of the method for preparing compound (A), R a R b and R c Independently, it is either hydrogen or fluorine. In some embodiments of the method for preparing compound (A), R a It is a halogen. In some embodiments of the method for preparing compound (A), R b It is a halogen. In some embodiments of the method for preparing compound (A), R c It is a halogen. In some embodiments of the method for preparing compound (A), R a R b and R c It is hydrogen.

[0122] In some embodiments of the method for preparing compound (A), P 2 It is a C1 to C6 alkyl group. In some embodiments of the method for preparing compound (A), P 2 It is tert-butyl.

[0123] In some embodiments of the method for preparing compound (A), P 3 and P 4 It is trimethylsilyl.

[0124] In some embodiments of the method for preparing a compound of formula (A), the compound of formula (A) is Or its pharmaceutically acceptable salt. In some embodiments of the method for preparing compound (A), compound (A) , dihydrochloride.

[0125] This document discloses a method for preparing compounds of formula (A), as outlined in Scheme 5: Option 5 This article discloses a method for preparing compound (B): The method uses a compound of formula (III) prepared by the method disclosed herein: ; in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be hydrogen, fluorine, or chlorine independently.

[0126] In some embodiments of the method for preparing compound (B), compound (III) is made: It reacts with (1S,2S,3R,5S)-(+)-pinenediol to form compound (IV): .

[0127] This article discloses a method for preparing compound (B): The method uses compounds of formula (IV) prepared by the method disclosed herein: ; in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be hydrogen, fluorine, or chlorine independently.

[0128] In some embodiments of the method for preparing compound (B), compound (IV) is made: It reacts with a carboxyl protecting agent to form a compound of formula (V): , where P 2 It is a carboxyl protecting group.

[0129] In some embodiments of the method for preparing compound (B), the carboxyl protecting agent is SOCl2, followed by NaOtBu.

[0130] In some embodiments of the method for preparing compound (B), compound (V) is made: It reacts with chloroiodomethane and a sterically hindered Grignard reagent to form a compound of formula (VI): .

[0131] In some embodiments of the method for preparing compound (B), the sterically hindered Grignard reagent is isopropyl magnesium chloride, cyclohexyl magnesium chloride, or isopropyl magnesium chloride:lithium chloride.

[0132] In some embodiments of the method for preparing compound (B), the sterically hindered Grignard reagent is isopropyl magnesium chloride:lithium chloride.

[0133] In some embodiments of the method for preparing compound (B), compound (VI) is made: The compound reacts with dichloromethane and a base, followed by a Lewis acid, to give compound (VII): .

[0134] In some embodiments of the method for preparing compound (B), the base is lithium diisopropylamino or 2,2,6,6-tetramethylpiperidinylmagnesium chloride:lithium chloride.

[0135] In some embodiments of the method for preparing compound (B), the base is lithium diisopropylamino.

[0136] In some embodiments of the method for preparing compound (B), the Lewis acid is ZnCl2.

[0137] In some embodiments of the method for preparing compound (B), compound (VII) is made: It reacts with a protected ammonium reagent to form a compound of formula (VIII): , where P 3 and P 4 It is an amine protecting group.

[0138] In some embodiments of the method for preparing compound (B), the protected ammonium reagent is a metal salt of hexaalkyldisilazane.

[0139] In some embodiments of the method for preparing compound (B), compound (VIII) is: It reacts with EtC(=O)Cl to form a compound of formula (X): .

[0140] In some embodiments of the method for preparing compound (B), compound (X) is: It reacts with a deprotecting agent to form a compound of formula (XI): .

[0141] In some embodiments of the method for preparing compound (B), the deprotecting agent is methanesulfonic acid.

[0142] In some embodiments of the method for preparing compound (B), compound (XI): and The reaction forms a compound of formula (XII): .

[0143] In some embodiments of the method for preparing compound (B), compound (XII) is: In the presence of alkali metal salts or quaternary ammonium salts of bromine or iodine, it reacts with propionyl chloride to form compound (B): .

[0144] In some embodiments of the method for preparing compound (B), the alkali metal salt of bromine is LiBr.

[0145] In some embodiments of the method for preparing compound (B), P 1 It is a C1 to C6 alkyl group. In some embodiments of the method for preparing compound (B), P 1 It is a methyl group.

[0146] In some embodiments of the method for preparing compound (B), R a R b and R c Independently, it is either hydrogen or fluorine. In some embodiments of the method for preparing compound (B), R a It is a halogen. In some embodiments of the method for preparing compound (B), R b It is a halogen. In some embodiments of the method for preparing compound (B), R c It is a halogen. In some embodiments of the method for preparing compound (B), R a R b and R c It is hydrogen.

[0147] In some embodiments of the method for preparing compound (B), P 2 It is a C1 to C6 alkyl group. In some embodiments of the method for preparing compound (B), P 2 It is tert-butyl.

[0148] In some embodiments of the method for preparing compound (B), P 3 and P 4It is trimethylsilyl.

[0149] In some embodiments of the method for preparing compound (B), compound (B) is Or its pharmaceutically acceptable salt.

[0150] This document discloses the preparation of compound (C) from compound (B) prepared by the method described herein: The method.

[0151] In some embodiments of the method for preparing compound (C), compound (B) is made: With R 1 The -OH reaction forms a compound of formula (C): , where R 1 It is optionally substituted C1 to C6 alkyl, optionally substituted C1 to C6 haloalkyl, optionally substituted C1 to C6 hydroxyalkyl, optionally substituted C1 to C6 aminoalkyl, optionally substituted C1 to C6 deuteralkyl, optionally substituted C1 to C6 heteroalkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C1 to C6 alkyl)cycloalkyl, optionally substituted (C1 to C6 alkyl)heterocycloalkyl, optionally substituted (C1 to C6 alkyl)aryl, or optionally substituted (C1 to C6 alkyl)heteroaryl.

[0152] In some embodiments of the method for preparing compound of formula (C), P 1 It is a C1 to C6 alkyl group. In some embodiments of the method for preparing compounds of formula (C), P 1 It is a methyl group.

[0153] In some embodiments of the method for preparing compound of formula (C), R a R b and R c Independently, it is either hydrogen or fluorine. In some embodiments of the method for preparing compounds of formula (C), R a It is a halogen. In some embodiments of the method for preparing compounds of formula (C), R b It is a halogen. In some embodiments of the method for preparing compounds of formula (C), R c It is a halogen. In some embodiments of the method for preparing compounds of formula (C), R a R b and R c It is hydrogen.

[0154] In some embodiments of the method for preparing compound of formula (C), P 2It is a C1 to C6 alkyl group. In some embodiments of the method for preparing compounds of formula (C), P 2 It is tert-butyl.

[0155] In some embodiments of the method for preparing compound of formula (C), P 3 and P 4 It is trimethylsilyl.

[0156] In some embodiments of the method for preparing compound of formula (C), R 1 It is an optionally substituted C1 to C6 alkyl, an optionally substituted C1 to C6 haloalkyl, or an optionally substituted C1 to C6 deuteralkyl. In some embodiments of the method for preparing compound (C), R 1 It is an optionally substituted C1 to C6 alkyl group. In some embodiments of the method for preparing compounds of formula (C), R 1 It is a C1 to C6 alkyl group. In some embodiments of the method for preparing compounds of formula (C), R 1 It is an ethyl group.

[0157] In some embodiments of the method for preparing a compound of formula (C), the compound of formula (C) is .

[0158] Combination Therapy This document describes a method for treating bacterial infections using a compound of formula (A), (B), or (C) or a pharmaceutically acceptable salt thereof prepared by any of the methods disclosed herein. In some embodiments, the compound of formula (A), (B), or (C) or a pharmaceutically acceptable salt thereof is used in combination with one or more antibiotics.

[0159] These methods can be used to inhibit bacterial growth under various conditions. In some embodiments, compounds of formula (A), (B), or (C), or pharmaceutically acceptable salts thereof, are administered to mammals, including humans, to prevent the growth of β-lactam-resistant bacteria in vivo. The term "resistance" is well known to those skilled in the art (see, for example, Payne et al., Antimicrobial Agents and Chemotherapy 38 767-772 (1994), Hanaki et al., Antimicrobial Agents and Chemotherapy 30 1120-1126 (1995)).

[0160] In some implementations, the infection being treated or prevented includes bacteria, such as Elizabethan meningococcus (…). Elizabethkingia meningoseptica ), Pseudomonas aeruginosa ( Pseudomonas aeruginosa ), fluorescent pseudomonas ( Pseudomonas fluorescens ), Pseudomonas acidophilus (Pseudomonas acidovorans ), Alcaligenes ( Pseudomonas alcaligenes ), Pseudomonas putida ( Pseudomonas putida ), Maltodextrin oligoaerobic bacteria ( Stenotrophomonas maltophilia Burkholderia cepacia (), Burkholderia cepacia Aeromonas hydrophila ( ) Aeromonas hydrophilia ), Escherichia coli ( Escherichia coli ), Citrobacter freundii ( Citrobacter freundii Salmonella typhimurium ( Salmonella typhimurium ), Salmonella typhi Salmonella typhi Salmonella paratyphi () Salmonella paratyphi Salmonella enteritidis ( ) Salmonella enteritidis ), Shigella dysenteriae ( Shigella dysenteriae Shigella flexneri ( Shigella flexneri Shigella somnifera ( Shigella sonnei Enterobacter cloacae () Enterobacter cloacae Enterobacter aerogenes ( Enterobacter aerogenes ), Klebsiella pneumoniae ( Klebsiella pneumoniae Klebsiella pneumoniae ( ) Klebsiella oxytoca Serratia marcescens ( ), Serratia marcescens ), Tulazelle Francisella ( Francisella tularensis Morganella morganii ( Morganella morganii ), Proteus mirabilis ( Proteus mirabilis ), common proteobacteria ( Proteus vulgaris ), Alcaligenes providediflora ( Providencia alcalifaciens Providencia retaliculata ( ), Providencia rettgeri Providencia stearothermia ( Providencia stuartii Acinetobacter baumannii ( Acinetobacter baumannii Acinetobacter calciacetate ( Acinetobacter calcoaceticus Acinetobacter hemolyticus ( Acinetobacter haemolyticus Yersinia enterocolitica (Yersinia enterocolitica) Yersinia enterocolitica Yersinia pestis (Yersinia pestis) Yersinia pestis Yersinia pseudotuberculosis ( Yersinia pseudotuberculosis Yersinia intermedia ( Yersinia intermedia Bordetella pertussis ( ), Bordetella pertussis Bordetella parapertussis ( ), Bordetella parapertussis ), Bordetella bronchiseptica ( Bordetella bronchiseptica Haemophilus influenzae ( ) Haemophilus influenzae Haemophilus parainfluenzae ( ) Haemophilus parainfluenzae Haemophilus hemolyticus ( Haemophilus haemolyticus ), Haemophilus parahaemolyticus ( Haemophilus parahaemolyticus ), Haemophilus dulcis ( Haemophilus ducreyi ), Pasteurella multocida ( Pasteurella multocida ), hemolytic Pasteurella ( Pasteurella haemolytica ), Branham's cocci ( Branhamella catarrhalis Helicobacter pylori ( Helicobacter pylori ), Campylobacter embryonicum ( Campylobacter fetus Campylobacter jejuni ( Campylobacter jejuni Campylobacter coli ( Campylobacter coli ), Breospirochete ( Borrelia burgdorferi ), Vibrio cholerae ( Vibrio cholerae ), Vibrio parahaemolyticus ( Vibrio parahaemolyticus Legionella pneumophila ( ) Legionella pneumophila Listeria monocytogenes ( Listeria monocytogenes ), Neisseria gonorrhoeae ( Neisseria gonorrhoeae ), Neisseria meningitidis ( Neisseria meningitidis ), genus *Aureobasidium* Kingella Moraxella spp. Moraxella Gardnerella vaginalis ( Gardnerella vaginalis Bacteroides fragilis ( Bacteroides fragilis Bacteroides gigantea ( Bacteroides distasonis Bacteroides 3452A homology group, Bacteroides commonis ( Bacteroides vulgatus ), Pseudomonas ovalis ( Bacteroides ovalus ), Bacteroides multiforme ( Bacteroides thetaiotaomicron ), Bacteroides monomorpha ( Bacteroides uniformis ), Bacteroides emblica ( Bacteroides eggerthii ), Visceral Bacteroides ( Bacteroides splanchnicus Clostridium difficile ( Clostridium difficile ), Mycobacterium tuberculosis ( Mycobacterium tuberculosis ), Mycobacterium avium ( Mycobacterium avium Intracellular mycobacteria ( Mycobacterium intracellulare Mycobacterium leprae ( Mycobacterium leprae Corynebacterium diphtheriae ( Corynebacteriumdiphtheriae Corynebacterium ulcerans ( Corynebacterium ulcerans Streptococcus pneumoniae () Streptococcus pneumoniae ), agalactococcus ( Streptococcus agalactiae Streptococcus pyogenes ( ) Streptococcus pyogenes ), Enterococcus faecalis ( Enterococcus faecalis ), Enterococcus faecalis ( Enterococcus faecium Staphylococcus aureus ( Staphylococcus aureus Staphylococcus epidermidis ( Staphylococcus epidermidis ), saprophytic Staphylococcus ( Staphylococcus saprophyticus Staphylococcus intermedia ( Staphylococcus intermedius ), Staphylococcus aureus subsp. suis ( Staphylococcus hyicus subsp. hyicus ), hemolytic staphylococci ( Staphylococcus haemolyticus Staphylococcus aureus ( Staphylococcus aureus ) or Staphylococcus aureus ( Staphylococcus saccharolytic ).

[0161] In some implementations, the infection being treated or prevented includes bacteria, such as Elizabethan meningococcus, Pseudomonas aeruginosa, Pseudomonas fluorescens, Maltodactylomiasis oligoanaerobic bacteria, Escherichia coli, Citrobacter flexneri, Salmonella typhimurium, Salmonella typhimurium, Salmonella paratyphimurium, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella soxehni, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella pneumoniae, Serratia marcescens, Acinetobacter calcareae, Acinetobacter hemolyticus, and Enterobacter cloacae. Yersinia enteritidis, Yersinia plague, Yersinia pseudotuberculosis, Yersinia intermediate, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus hemolyticus, Haemophilus parahemolyticus, Helicobacter pylori, Campylobacter embryonicus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella spp., Bacteroides fragilis, Bacteroides vulgaris, Pseudomonas ovalis, Bacteroides polymorpha, Bacteroides monomorpha, Bacteroides escherichiae, or Bacteroides viscera.

[0162] Another aspect provided herein is a method for treating bacterial infections, comprising administering to a subject a pharmaceutical composition comprising a compound of formula (A), (B), or (C), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra-abdominal infection, or a skin infection.

[0163] In some implementations, bacterial infections include complicated intra-abdominal infections (including peritonitis and abscesses), complicated urinary tract infections (including pyelonephritis), uncomplicated urinary tract infections (including cystitis), pneumonia, genitourinary infections (including urethritis, cervicitis, and pelvic inflammatory disease), uncomplicated skin and skin structure infections, complicated skin and skin structure infections (including diabetic foot infections), and bone infections (including osteomyelitis).

[0164] In some implementations, bacterial infection is a lower respiratory tract infection (including bronchitis, acute bacterial exacerbation of chronic bronchitis (ABECB), community-acquired bacterial pneumonia, hospital-acquired bacterial pneumonia, including ventilator-associated pneumonia and ventilator-associated pneumonia).

[0165] In some implementations, the bacterial infection is an upper respiratory tract infection, including acute bacterial otitis media, sinusitis, pharyngitis, or tonsillitis.

[0166] In some implementations, the bacterial infection is enteritis or gastroenteritis, gonorrhea, meningitis, or Lyme disease.

[0167] In some embodiments, the antibiotic is a β-lactam antibiotic. In some embodiments, the β-lactam antibiotic is a penicillin, cephalosporin, carbapenem, cephamycin, monocycline, or a combination thereof.

[0168] In some implementation schemes, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra-abdominal infection, or a skin infection. Penicillins include, but are not limited to, amoxicillin, ampicillin, azithromycin, azoxycillin, bamoxicillin, benzathine penicillin, benzathine phenoxymethylpenicillin, benzylpenicillin (G), carbenicillin, carindocillin, cloxacillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, mecillin, metancillin, methicillin, mezlocillin, nafcillin, oxacillin, penicillin, fenescillin, phenoxymethylpenicillin (V), piperacillin, piampicillin, piampicillin, procaine penicillin, propipillin, sulfadiazine, phthalimide, temoxicillin, and ticarcillin. Penicillenes include, but are not limited to, faropenem. Carbapenems include, but are not limited to, biapenem, ertapenem, doribenem, imipenem, meropenem, and panipenem. Cephalosporins / cephamycins include, but are not limited to, cefazolin, cefaclor, cefadroxil, cefalexin, cefotaxime, cefotaxime, cefamandole, cefepime, ceftrazine, cefotaxime, cefoxitin, cefazolin, cefadroxil, cefoperazone, cefazodone, cefadroxil, cefacarpin, cefodamide, cefdinir, ceftoran, cefepime, cefotaxime, cefotaxime, cefotiam, cefotaxime, cefmetazole, cefminox, cefdinir, cefoperazone, and cefoperazone. The following are listed as examples of antibiotics: Cefalexin, Cefotaxime, Cefotetan, Cefotetan, Cefoxitin, Cefazolin, Cefimazole, Cefpirome, Cefpirome, Cefpodoxime, Cefprozil, Cefquinoxime, Cefquinolone, Cefradine, Cefsarim, Cefsulfuron-methyl, Cefrophosphine, Ceftazidime, Cefterfenadine, Cefotetan, Cefotetan, Cefbufenoxuron, Ceftiofur, Ceftiofur, Cefazolin, Cefazolin, Ceftobiprole, Ceftriaxone, Cefuroxime, Cefazolin, Fluoxetine, Latamoxef, and Chlorfenapyr. Monocyclines include, but are not limited to, Aztreonam, Carrumonam, Nocardicin A, and Tegamonam.

[0169] In some embodiments, the β-lactam antibiotic is cefepime or a pharmaceutically acceptable salt thereof. In some embodiments, the β-lactam antibiotic is cefbufen or a pharmaceutically acceptable salt thereof.

[0170] This invention provides, but is not limited to, the following embodiments: 1. A method for preparing compounds of formula (III): Methods; in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be independently hydrogen, fluorine, or chlorine; The method includes using a compound of formula (II): It reacts with oxidizing agents.

[0171] 2. The method according to Embodiment 1, wherein the oxidant is potassium permanganate (KMnO4).

[0172] 3. The method according to embodiment 1 or 2, wherein the method further includes an alkali.

[0173] 4. The method according to any one of embodiments 1 to 3, wherein the method comprises: (i) The compound of formula (II): Suspended in water; (ii) Add a base to dissolve the compound of formula (II) in water; (iii) Add the oxidant while stirring; (iv) Stir; (v) Add solvent to deactivate excess oxidant; (vi) To stir; (vii) Filter to obtain filtrate; (viii) Acidify the filtrate to obtain a slurry; (viii) Cooling the slurry; and (ix) Filter the slurry to obtain the compound of formula (III): .

[0174] 5. The method according to embodiment 4, wherein the base in step (ii) is sodium hydroxide.

[0175] 6. The method according to embodiment 4 or 5, wherein the oxidant is potassium permanganate (KMnO4).

[0176] 7. The method according to any one of embodiments 4 to 6, wherein step (iii) is performed for about 10 hours to about 20 hours.

[0177] 8. The method according to any one of embodiments 4 to 7, wherein step (iii) is performed for approximately 16 hours.

[0178] 9. The method according to any one of embodiments 4 to 8, wherein the temperature in step (iii) is maintained between about 20°C and about 30°C.

[0179] 10. The method according to any one of embodiments 4 to 9, wherein the solvent that deactivates the excess oxidant is a primary alcohol solvent or a secondary alcohol solvent.

[0180] 11. The method according to any one of embodiments 4 to 10, wherein the solvent that deactivates the excess oxidant is ethanol.

[0181] 12. The method according to any one of embodiments 4 to 11, wherein step (vi) is performed for about 10 minutes to about 2 hours.

[0182] 13. The method according to any one of embodiments 4 to 12, wherein step (vi) is performed for about 30 minutes.

[0183] 14. The method according to any one of embodiments 4 to 13, wherein, prior to acidification, the filtrate obtained in step (vii) is cooled to between about 0°C and about 10°C in step (viii).

[0184] 15. The method according to any one of embodiments 4 to 14, wherein the filtrate is cooled to about 5°C in step (viii) before acidification.

[0185] 16. The method according to any one of embodiments 4 to 15, wherein the acid used for acidification is sulfuric acid.

[0186] 17. The method according to any one of embodiments 4 to 16, wherein the compound of formula (III) is obtained by filtration.

[0187] 18. The method according to embodiment 1, wherein the compound of formula (II): It is achieved by making compound (I): It is obtained by reacting with a lithium reagent, followed by a reaction with a borate ester.

[0188] 19. The method according to embodiment 18, wherein the compound of formula (I) is contacted with the lithium reagent to form the compound of formula (Ia): .

[0189] 20. The method according to embodiment 19, wherein the compound of formula (Ia) is not isolated.

[0190] 21. The method according to embodiment 19 or 20, wherein the compound of formula (Ia) is further reacted with the borate ester to form the compound of formula (II).

[0191] 22. The method according to any one of embodiments 18 to 21, wherein the lithium reagent is n-BuLi.

[0192] 23. The method according to any one of embodiments 18 to 21, wherein the borate ester is B(OiPr)3.

[0193] 24. The method according to embodiment 18, wherein the method includes: (i) Compounds of formula (I): Combined with diamine in solvent; (ii) Stirring; (iii) Add lithium reagent; (iv) Stir; (v) Add borate ester; (vi) Quenching the reaction by adding an acidic aqueous solution; (vii) Separate the layers to obtain the organic layer; (viii) Add an alkaline aqueous solution to the organic layer; (ix) Separate the layers to obtain the water layer; (x) Add acid to the aqueous layer; (xi) Cooling to obtain a suspension; (xii) To stir; (xiii) Filter the suspension to obtain the compound of formula (II): .

[0194] 25. The method according to embodiment 24, wherein the diamine is TMEDA.

[0195] 26. The method according to embodiment 24 or 25, wherein the solvent used in step (i) is cyclohexane.

[0196] 27. The method according to any one of embodiments 24 to 26, wherein the lithium reagent is nBuLi.

[0197] 28. The method according to any one of embodiments 24 to 27, wherein the borate ester is B(OiPr)3.

[0198] 29. The method according to any one of embodiments 24 to 28, wherein the addition of the lithium reagent in step (iii) is carried out over a period of about 1 hour to about 6 hours.

[0199] 30. The method according to any one of embodiments 24 to 29, wherein the addition of the lithium reagent in step (iii) is carried out while maintaining the temperature between about 0°C and about 20°C.

[0200] 31. The method according to any one of embodiments 24 to 30, wherein step (iv) is performed for about 2 hours to about 3 hours.

[0201] 32. The method according to any one of embodiments 24 to 31, wherein the temperature is cooled to below -70°C prior to the addition of the borate ester in step (v).

[0202] 33. The method according to any one of embodiments 24 to 32, wherein after the addition of the borate ester in step (v), the temperature is raised to above -20°C.

[0203] 34. The method according to any one of embodiments 24 to 33, wherein the acidic aqueous solution in step (vi) is an HCl solution.

[0204] 35. The method according to any one of embodiments 24 to 32, wherein the alkaline aqueous solution in step (viii) is a NaOH solution.

[0205] 36. The method according to any one of embodiments 24 to 32, wherein the cooling temperature in step (xi) is about 0°C and about 5°C.

[0206] 37. The method according to embodiment 1 further comprises making the compound of formula (III): It reacts with (1S,2S,3R,5S)-(+)-pinenediol in a solvent to form compound (IV): .

[0207] 38. The method according to embodiment 37, wherein the solvent is n-heptane.

[0208] 39. The method according to embodiment 37 or 38, wherein the method includes: (i) The compound of formula (III), (1S,2S,3R,5S)-(+)-pinenediol and the solvent are mixed; (ii) The mixture obtained by heating; (iii) Cooling to obtain a slurry; (iv) Filtration to obtain the compound of formula (IV).

[0209] 40. The method according to embodiment 39, wherein the solvent is n-heptane.

[0210] 41. The method according to embodiment 39 or 40, wherein the heating is performed to achieve reflux.

[0211] 42. The method according to any one of embodiments 39 to 41, wherein step (ii) further includes removing water.

[0212] 43. The method according to any one of embodiments 39 to 42, wherein the cooling temperature in step (iii) is below about 60°C.

[0213] 44. A method for preparing compound (A): The method uses a compound of formula (III) prepared by any one of embodiments 1 to 17: ; in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be hydrogen, fluorine, or chlorine independently.

[0214] 45. The method according to embodiment 44, wherein the compound of formula (III): It reacts with (1S,2S,3R,5S)-(+)-pinenediol to form compound (IV): .

[0215] 46. ​​The method according to embodiment 45, wherein the compound of formula (IV): It reacts with the carboxyl protecting group to form a compound of formula (V): , where P 2 It is a carboxyl protecting group.

[0216] 47. The method according to embodiment 46, wherein the carboxyl protecting agent is SOCl2, followed by NaOtBu.

[0217] 48. The method according to embodiment 46 or 47, wherein the compound of formula (V): It reacts with chloroiodomethane and a sterically hindered Grignard reagent to form a compound of formula (VI): .

[0218] 49. The method according to embodiment 48, wherein the sterically hindered Grignard reagent is isopropyl magnesium chloride, cyclohexyl magnesium chloride, or isopropyl magnesium chloride:lithium chloride.

[0219] 50. The method according to embodiment 48 or 49, wherein the sterically hindered Grignard reagent is isopropyl magnesium chloride:lithium chloride.

[0220] 51. The method according to any one of embodiments 48 to 50, wherein the compound of formula (VI): The compound reacts with dichloromethane and a base, followed by a Lewis acid, to give compound (VII): .

[0221] 52. The method according to embodiment 51, wherein the base is lithium diisopropylamino or 2,2,6,6-tetramethylpiperidinylmagnesium chloride:lithium chloride.

[0222] 53. The method according to embodiment 51 or 52, wherein the base is lithium diisopropylamino.

[0223] 54. The method according to any one of embodiments 51 to 53, wherein the Lewis acid is ZnCl2.

[0224] 55. The method according to any one of embodiments 51 to 54, wherein the compound of formula (VII) is: It reacts with a protected ammonium reagent to form a compound of formula (VIII): , where P 3 and P 4 It is an amine protecting group.

[0225] 56. The method according to embodiment 55, wherein the protected ammonium reagent is a metal salt of hexaalkyldisilazane.

[0226] 57. The method according to embodiment 55 or 56, wherein the compound of formula (VIII): and The reaction forms a compound of formula (IX): .

[0227] 58. The method according to embodiment 57, wherein the method further comprises a coupling agent.

[0228] 59. The method according to embodiment 58, wherein the coupling agent is HATU, EDC, HBTU, HCTU, HOBt, PyAOP, PyBOP or TBTU.

[0229] 60. The method according to embodiment 58 or 59, wherein the coupling agent is HATU.

[0230] 61. The method according to any one of embodiments 57 to 60, wherein the compound of formula (IX) is: It reacts with acid to form a compound of formula (A): Or its pharmaceutically acceptable salt.

[0231] 62. A preparation method for compound (B): The method uses a compound of formula (III) prepared by any one of embodiments 1 to 17: ; in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be hydrogen, fluorine, or chlorine independently.

[0232] 63. The method according to embodiment 62, wherein the compound of formula (III): It reacts with (1S,2S,3R,5S)-(+)-pinenediol to form compound (IV): .

[0233] 64. The method according to embodiment 63, wherein the compound of formula (IV): It reacts with a carboxyl protecting agent to form a compound of formula (V): , where P 2 It is a carboxyl protecting group.

[0234] 65. The method according to embodiment 64, wherein the carboxyl protecting agent is SOCl2, followed by NaOtBu.

[0235] 66. The method according to embodiment 63 or 64, wherein the compound of formula (V): It reacts with chloroiodomethane and a sterically hindered Grignard reagent to form a compound of formula (VI): .

[0236] 67. The method according to embodiment 66, wherein the sterically hindered Grignard reagent is isopropyl magnesium chloride, cyclohexyl magnesium chloride, or isopropyl magnesium chloride:lithium chloride.

[0237] 68. The method according to embodiment 66 or 67, wherein the sterically hindered Grignard reagent is isopropyl magnesium chloride:lithium chloride.

[0238] 69. The method according to any one of embodiments 66 to 68, wherein the compound of formula (VI): The compound reacts with dichloromethane and a base, followed by a Lewis acid, to give compound (VII): .

[0239] 70. The method according to embodiment 69, wherein the base is lithium diisopropylamino or 2,2,6,6-tetramethylpiperidinylmagnesium chloride:lithium chloride.

[0240] 71. The method according to embodiment 69 or 70, wherein the base is lithium diisopropylamino.

[0241] 72. The method according to any one of embodiments 69 to 71, wherein the Lewis acid is ZnCl2.

[0242] 73. The method according to any one of embodiments 69 to 72, wherein the compound of formula (VII) is: It reacts with a protected ammonium reagent to form a compound of formula (VIII): , where P 3 and P 4 It is an amine protecting group.

[0243] 74. The method according to embodiment 73, wherein the protected ammonium reagent is a metal salt of hexaalkyldisilazane.

[0244] 75. The method according to embodiment 73 or 74, wherein the compound of formula (VIII): It reacts with EtC(=O)Cl to form a compound of formula (X): .

[0245] 76. The method according to embodiment 75, wherein the compound of formula (X): It reacts with a deprotecting agent to form a compound of formula (XI): .

[0246] 77. The method according to embodiment 76, wherein the deprotecting agent is methanesulfonic acid.

[0247] 78. The method according to embodiment 76 or 77, wherein the compound of formula (XI): and The reaction forms a compound of formula (XII): .

[0248] 79. The method according to embodiment 78, wherein the compound of formula (XII): In the presence of alkali metal salts or quaternary ammonium salts of bromine or iodine, it reacts with propionyl chloride to form compound (B): .

[0249] 80. The method according to embodiment 79, wherein the alkali metal salt of bromine is LiBr.

[0250] 81. The method according to embodiment 79 or 80, wherein the compound of formula (B) is: With R 1 The -OH reaction forms a compound of formula (C): , where R 1 It is optionally substituted C1 to C6 alkyl, optionally substituted C1 to C6 haloalkyl, optionally substituted C1 to C6 hydroxyalkyl, optionally substituted C1 to C6 aminoalkyl, optionally substituted C1 to C6 deuteralkyl, optionally substituted C1 to C6 heteroalkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C1 to C6 alkyl)cycloalkyl, optionally substituted (C1 to C6 alkyl)heterocycloalkyl, optionally substituted (C1 to C6 alkyl)aryl, or optionally substituted (C1 to C6 alkyl)heteroaryl.

[0251] 82. The method according to any one of embodiments 1 to 81, wherein P 1 It is a C1 to C6 alkyl group.

[0252] 83. The method according to any one of embodiments 1 to 82, wherein P 1 It is a methyl group.

[0253] 84. The method according to any one of embodiments 1 to 83, wherein R a R b and R c It can be either hydrogen or fluorine.

[0254] 85. The method according to any one of embodiments 1 to 84, wherein R a R b and R c It is hydrogen.

[0255] 86. The method according to any one of embodiments 1 to 85, wherein P 2 It is a C1 to C6 alkyl group.

[0256] 87. The method according to any one of embodiments 1 to 86, wherein P 2 It is tert-butyl.

[0257] 88. The method according to any one of embodiments 56 to 87, wherein P 3 and P 4 It is trimethylsilyl.

[0258] 89. The method according to any one of embodiments 81 to 88, wherein R 1It is an optionally substituted C1 to C6 alkyl, an optionally substituted C1 to C6 haloalkyl, or an optionally substituted C1 to C6 deuterated alkyl.

[0259] 90. The method according to any one of embodiments 81 to 89, wherein R 1 It is an optional substituted C1 to C6 alkyl group.

[0260] 91. The method according to any one of embodiments 81 to 90, wherein R 1 It is a C1 to C6 alkyl group.

[0261] 92. The method according to any one of embodiments 81 to 91, wherein R 1 It is an ethyl group.

[0262] 93. The method according to any one of embodiments 45 to 62, wherein the compound of formula (A) is Or its pharmaceutically acceptable salt.

[0263] 94. The method according to any one of embodiments 63 to 80, wherein the compound of formula (B) is .

[0264] 95. The method according to embodiment 81, wherein the compound of formula (C) is .

[0265] Example All chemicals, reagents and solvents were purchased from commercial sources when available and were used without further purification.

[0266] The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications or alterations are included within the scope of this disclosure and the appended claims.

[0267] Example 1 Step 1 and the boronization of 2-2-methylanisole The scale-up was initiated using 40 kg (324 mol, 1 equivalent) of 2-methylanisole (1), 50 kg of TMEDA (1.3 equivalent), and 60 kg of cyclohexane. A solution of n-butyllithium (23% hexane solution, 115 kg, 1.3 equivalent) was added at 5–10 °C, and after complete addition, the pipeline was flushed with 30 kg of cyclohexane. After 1 hour at up to 10 °C, process control (IPC) by HPLC with UV / Vis detection showed 20% area of ​​unreacted 2-methylanisole (peak at 10 min). The mixture was stirred at 5–20 °C for approximately 6 hours in total. At this point, IPC showed 10% area of ​​residual 2-methylanisole.

[0268] Cool the batch to -75°C and add MTBE (230 kg) at <-30°C during cooling. Add triisopropyl borate (90 kg, 1.5 equivalent) at <-70°C and slowly heat the batch to -20°C.

[0269] At this temperature, the mixture was transferred to a quenching reactor containing a 15% aqueous hydrochloric acid solution (315 kg). IPC showed residual 2-methylanisole at an area level of 6%.

[0270] Subsequently, the phases were separated, and the organic layer was combined with water (240 kg) and 33% NaOH (53 kg), and the layers were separated again. IPC did not show a significant product content in the organic layer.

[0271] The aqueous solution of the product was acidified and stirred at <5°C for 2 hours. A sample was removed and filtered in the laboratory, showing a product content of approximately 1% wt in the mother liquor and a surface purity of 99.7% for the solid product. Therefore, this batch was released for filtration.

[0272] The product (2,48.5 kg; LOD: 21%) was further pulped with water (280 kg), filtered, and the filter cake was washed with water (50 kg). The wet product obtained from this washing showed the expected purity (99.9% area).

[0273] 42 kg of moist intermediate 2 was obtained. The sample (27 g) was dried overnight in the laboratory, showing a loss on drying (LOD) of approximately 12%. The dried product obtained by HPLC showed an efficacy of 103.6%. Therefore, the yield of this step was calculated to be 38.3 kg (71%) of 2-methoxy-3-methylphenylboronic acid.

[0274] Step 3 - KMnO4 oxidation Intermediate 2 (approximately 38 kg of dried product) was suspended in water (280 kg) and dissolved by adding 33% NaOH solution (69 kg). KMnO4 (total 100 kg) was added starting with 5 kg portions via solid-state locking. After partial addition, the observed exothermic effect was well consistent with the expected value of approximately 0.8 to 1 °C / kg. After adding 30 kg, it was converted to a 10 kg portion. Samples taken after 40 kg showed the expected conversion level. The internal temperature was maintained at ≤35 °C, and the addition was completed over 18 hours. The next day, IPC showed complete (99.7% area) conversion, and the reaction was quenched by adding ethanol. After stirring for 1 to 2 hours, the sample was filtered in the laboratory, showing a colorless filtrate. The bulk was filtered and the MnO2 filter cake was washed with 120 kg of 1% NaOH and 50 kg of water, yielding 530 kg of combined filtrate. HPLC analysis of the filtrate showed a product content of 7.92%, equivalent to 42 kg of 3-carboxy-2-methoxyphenylboronic acid (93.5% of the theoretical value). The filtrate was acidified by adding 37% sulfuric acid (121 kg) until the pH reached 1.3. The slurry was cooled to 0-5°C, filtered, and the filter cake was washed with water (150 kg).

[0275] Wet intermediate 3 (42.2 kg) exhibiting a 19% LOD was isolated. This equates to 34.2 kg of pure intermediate 3 (76%). Additionally, a certain amount of product (2 to 3 kg) adhered to the reactor wall. Therefore, the actual yield of this reaction is expected to be at least 36 kg (80%). Internal analysis showed that the HPLC purity of wet intermediate 3 was 99.9%, with only impurities of 2-anesicin and the intermediate from step 1 detected (both less than 0.1%).

[0276] Step 4: Formation of pinanediol ester Pinanediol ester formation was carried out in the same reactor used for separating intermediate 3, without washing. During the reaction, intermediate 3 adhered to the reactor wall (expected up to 3 kg; 15.3 mol). Additionally, 36.5 kg of wet intermediate 3 (approximately 29.6 kg of pure intermediate, 151.0 mol) and 30.0 kg of (+)-pinediol (176.2 mol, 1.1 equivalent) were added. The solids were suspended in n-heptane (290 kg), the mixture was heated to reflux, and water was removed by distillation. After stirring overnight, intermediate 3 remained on the reactor wall. Additional n-heptane (210 kg) was added to increase the packing level, and reflux was continued under reduced pressure. However, intermediate 3 remained, which was not absorbed by the n-heptane. Samples obtained after crystallization showed no remaining intermediate 3. Q-NMR analysis of the mother liquor (approximately 500 kg) revealed an excess of approximately 3.8 kg of unreacted pinanediol and 4.3 kg of product. Based on the amount of pinanediol used, 50.9 kg of the desired product 4 was formed. Accordingly, approximately 46.6 kg of product remained in suspension.

[0277] Product 4 was filtered and washed with heptane (30 kg). It was dried on the filter overnight, yielding 44.1 kg of the desired product (LOD: 0.04%, 88% yield based on the wet product used).

[0278] After completion, the reactor was washed with THF, and the washing solution showed approximately 2 kg of the desired product 4 and a small amount of intermediate 3 (approximately 0.5 kg).

Claims

1. A method for preparing compounds of formula (III): Methods; in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be independently hydrogen, fluorine, or chlorine; The method includes using a compound of formula (II): It reacts with oxidizing agents.

2. The method according to claim 1, wherein the oxidant is potassium permanganate (KMnO4).

3. The method according to claim 1 or 2, wherein the method further comprises an alkali.

4. The method according to any one of claims 1 to 3, wherein the method comprises: (i) The compound of formula (II): Suspended in water; (ii) Add a base to dissolve the compound of formula (II) in water; (iii) Add the oxidant while stirring; (iv) Stir; (v) Add solvent to deactivate excess oxidant; (vi) To stir; (vii) Filter to obtain filtrate; (viii) Acidify the filtrate to obtain a slurry; (viii) Cool the slurry; as well as (ix) Filter the slurry to obtain the compound of formula (III): .

5. The method according to claim 4, wherein the base in step (ii) is sodium hydroxide.

6. The method of claim 4, wherein the compound of formula (III) is obtained by filtration.

7. The method according to claim 1, wherein the compound of formula (II) is: It is achieved by making compound (I): It is obtained by reacting with a lithium reagent, followed by a reaction with a borate ester.

8. The method of claim 7, wherein the method comprises: (i) Compounds of formula (I): Combined with diamine in solvent; (ii) Stirring; (iii) Add lithium reagent; (iv) Stir; (v) Add borate ester; (vi) Quenching the reaction by adding an acidic aqueous solution; (vii) Separate the layers to obtain the organic layer; (viii) Add an alkaline aqueous solution to the organic layer; (ix) Separate the layers to obtain the water layer; (x) Add acid to the aqueous layer; (xi) Cooling to obtain a suspension; (xii) To stir; (xiii) Filter the suspension to obtain the compound of formula (II): .

9. A method for preparing compound of formula (A): The method uses a compound of formula (III) prepared by any one of claims 1 to 6: ; in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be hydrogen, fluorine, or chlorine independently.

10. A preparation of compound (B): The method uses a compound of formula (III) prepared by any one of claims 1 to 6: ; in: P 1 It is a hydroxyl protecting group; and R a R b and R c It can be hydrogen, fluorine, or chlorine independently.

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