Method of preparing boric acid derivative serving as beta-lactamase inhibitor

Abstract

Provided is a method for preparing a boric acid derivative serving as a beta-lactamase inhibitor. Specifically, provided is a method for preparing a compound as shown in general formula (I-3) or a pharmaceutically acceptable salt thereof. The preparation method features a simple process route and can reduce production costs while ensuring safe production.

Description

Preparation method of boric acid derivatives as β-lactamase inhibitors Technical Field

[0001] This disclosure pertains to the pharmaceutical field, specifically relating to a method for preparing a boric acid derivative as a β-lactamase inhibitor. Background Technology

[0002] β-lactam antibiotics are the most widely used and most effective class of antibacterial drugs in clinical practice. Currently, the most important antibiotics available are several classes of compounds containing a β-lactam ring, including penicillins, penicillenes, carbapenems, cephalosporins, monocyclic lactams, and sulfactams. These β-lactam antibiotics inhibit cell wall biosynthesis by binding to a protein called penicillin-binding protein (PBP), which is essential for the synthesis of peptidoglycan, a major component of the cell walls of both Gram-negative and Gram-positive bacteria.

[0003] Although β-lactam antibiotics remain very important worldwide, resistance to β-lactamase-based antibiotics in various infectious pathogens reduces the effectiveness of treatment for bacterial infections. The most significant resistance mechanism is the production of type A, C, and D β-lactamases with serine residues at their active sites. These enzymes can break down β-lactam antibiotics, leading to inactivation of their antibacterial activity. Type A β-lactamases have primary substrate specificity against penicillin-based drugs, while type C β-lactamases have primary substrate specificity against cephalosporin-based drugs. Commercially available β-lactamase inhibitors include clavulanic acid, sulbactam, and tazobactam. These inhibitors are primarily effective against type A β-lactamase-producing bacteria and are used in combination with penicillin-based antibiotics. However, more than 250 β-lactamases have been reported to date. Among them, in addition to the spread of type C β-lactamases and extended-spectrum β-lactamases (ESBLs) belonging to types A and D, drug-resistant bacteria of type A, such as KPC-2, which produce carbapenems that even break down carbapenems, which are the last barrier against β-lactam antibiotics, are also considered a problem.

[0004] In recent years, novel β-lactamase inhibitors have become a hot topic of development, such as QPX-7728 and VNRX-5133. WO2014107536, WO2014089365, WO2018005662, and WO2019226931 disclose a series of β-lactamase inhibitors, with the aim of improving resistance to β-lactamase inhibitors.

[0005] WO2022218328A discloses a boric acid derivative of a β-lactamase inhibitor, having the following structure:

[0006] In view of simplifying the preparation process, reducing production costs and improving production safety, this disclosure provides a new method for preparing the aforementioned boric acid derivatives. Summary of the Invention

[0007] This disclosure provides a method for processing the compound shown in (I) or a pharmaceutically acceptable salt thereof.

[0008] The method includes the following steps:

[0009] Organic boron intermediates The compound is combined with one or more chiral auxiliaries to form a chiral complex intermediate, said chiral auxiliaries being selected from (S)-(-)-2-phenylglycine, (S,S)-(-)-2-amino-1,2-diphenylethanol, (S)-(+)-phenyl-1,2-ethylenediol, (1S,2R)-2-amino-1,2-diphenylethanol, and (S)-(+)-2-phenylglycine; thereby converting the chiral complex into a compound of formula (I-3).

[0010] in:

[0011] Y is independently selected from CH2, NH, O, and S;

[0012] R1 is a carboxylic acid protecting group;

[0013] R2 is OH or optionally substituted -OC 1-6 alkyl;

[0014] R c Selected from the following groups with optional substitution: C1-C6 alkyl, halogen, deuterium, hydroxyl, mercapto, -NR i R j , oxygen group, thio group, -C(O)R k -C(O)OR k -S(O)R k -S(O)OR k -S(O)(O)R k -S(O)(O)OR k -C(S)R k Nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 7- to 10-membered fused cycloalkyl, 7- to 10-membered fused heterocyclic, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused cycloaryl, 5- to 12-membered heteroaryl;

[0015] n is selected from 1, 2, 3, 4, 5, or 6;

[0016] m is selected from 0, 1, 2, 3, 4, 5 or 6.

[0017] In some embodiments, the chiral auxiliaries are selected from (S)-(-)-2-phenylglycine and (S,S)-(-)-2-amino-1,2-diphenylethanol.

[0018] In some embodiments, the conversion of the chiral complex includes reacting the chiral complex with a cyclopropane oxidizing agent.

[0019] In some embodiments, the cyclopropanating agent comprises CH2I2 or CH2Br2, and one or more metal compounds. In some embodiments, the cyclopropanating agent comprises CH2I2. In some embodiments, the cyclopropanating agent comprises CH2Br2. In some embodiments, the metal compound comprises one or more metals selected from zinc, copper, samarium, aluminum, and silver. In some embodiments, the metal compound may be Zn / Cu, Zn / Ag, Sm / Hg, ZnEt2, or a mixture of Zn and CuCl.

[0020] In some embodiments, the cyclopropanating agent includes CH2I2 and Zn / Cu. In some embodiments, the cyclopropanating agent includes CH2Br2, Zn, and CuCl. In some embodiments, the cyclopropanating agent includes ZnEt2 and CH2I2.

[0021] This disclosure also provides a method for preparing the compound of formula (I) or a salt thereof, comprising the step of hydrolyzing the compound of formula (I-3) into the compound of formula (I).

[0022] In some implementations, the hydrolysis step is carried out under alkaline conditions.

[0023] In some embodiments, the reagents for the alkaline conditions include, but are not limited to, LiOH, NaOH, and KOH, with NaOH being preferred.

[0024] In some embodiments, the method further includes: in the presence of an alkaline system, formula (IV) The compound reacts with a boriding agent to form formula (I-1). The steps for obtaining organoboron intermediates.

[0025] The borizing agent can be any borizing agent suitable for introducing boron atoms into the furan ring. In some embodiments, the borizing agent is (R4O)2B-B(OR4)2, wherein each R4 is independently H, optionally substituted C. 1-6 Alkyl group, or two R4 groups together, are optionally substituted C4 groups. 2-4The alkylene chain forms an optionally substituted 5- to 7-membered heterocyclic ring with an intermediate atom. In some embodiments, the borizing agent is (HO)₂B-B(OH)₂. In some embodiments, the borizing agent is selected from B₂(Pin)₂ (bis(pinacol)diboron), B₂(Cat)₂ (bis(catechol)diboron), and B₂neop₂ (bis(neopentylethylene glycol)diboron). In some embodiments, the borizing agent is B₂(Pin)₂.

[0026] In some embodiments, a nickel catalyst precursor and ligand are combined to form a nickel catalyst prior to reacting the compound of formula (IV) with the boriding agent in a solvent system and an alkaline system. In some embodiments, the nickel catalyst precursor and ligand are combined to form a nickel catalyst in the presence of the compound of formula (IV) with the boriding agent in a solvent system and an alkaline system.

[0027] In some embodiments, the nickel catalyst precursor is selected from NiCl2, Ni(acac)2, and Ni(COD)2. In some embodiments, the nickel catalyst precursor is NiCl2 or Ni(Acac)2. In some embodiments, the nickel catalyst precursor is NiCl2.

[0028] In some embodiments, the ligand or catalyst is selected from bis(di-cyclopentylphosphonium)ethyltetrafluoroborate, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 2,2'-bis(dicyclohexylphosphinoalkyl)-1,1'-biphenyl, 1,2-bis((di-tert-butylphosphinoalkyl)methyl)benzene, 1,3-bis(1-adamantyl)imidazolium, 1,3-di-tert-butylimidazolium, 1,3-bis(2,6-diisopropyl-phenyl)-4,5-dihydroimidazolium-2-ylene, 1,3-bis(2,6-diisopropylphenyl)-1H-imidazolium-3-on-2-ylene, P(octyl)3, Dppf, DiPrf, dcype, JosiPhos 9-1. (S,S,R,R)-TangPhos, (S,S,R,R)-DuanPhos, DavePhos, P(tBu)3, P(n-Bu)3, P(n-Pr)3, antPhos, (tBu)XantPhos, (R)-SegPhos, (R)-DM-SegPhos, (R)-MeOBIPHEP, (R,S)-BinaPhos, B inaphane, Phosphoramidite, (S)-SegphosRu(Oac)2, trans-PdCl2(Pcy3)2, [Rh(S,S)EtDuPhos(COD)]Otf, (S)-XylylPhanePhos, (R)-C3-TunePhos, (R)-DTBM-Garphos, (R)-DMM-Garphos, (R (R,R)-Xyl-SKP, Thio-XantPhos, TaniaPhos, SPANPhos, Tris(4-methoxyphenyl)phosphine, Tris(2,6-dimethoxyphenyl)phosphine, Bis(dicyclohexylphosphine)methane, DCYPE, 1,3-Bis(dicyclohexylphosphine)propane, 1,2-Bis(diphenylphosphine)ethane, (R,R)-Dipamp, Bis(dicyclohexylphosphine)ether, DPEPhos, Bis (2-Diphenylphosphinoethyl)phenylphosphine, 1,1,1-tris(diphenylphosphinomethyl)ethane, DPPF, 1,1′-ferrocene di-bis(dicyclohexylphosphine), DTBPF, DiPrF, 1-diphenylphosphino-1′-(di-butylphosphino)ferrocene, HiersoPhos, iPr(NHC), SIMES, IMES, (1,3-bis[bis(o-methoxyphenyl)phosphino]propane and P(n-Bu)3)2. In some embodiments, the ligand is P(octyl)3, P(n-Pr)3, P(n-Bu)3, diPrf, or dcype. In some embodiments, the ligand is P(n-Bu)3. In some embodiments, the ligand is P(n-Pr)3.

[0029] In some embodiments, the nickel catalyst may be selected from: NiCl2(PPh3)2, NiCl2(PCy2Ph)2, NiCl2(PPh2CH2CH2PPh2), NiCl2(1,3-bis(diphenylphosphine)propane), NiCl2(1,3-bis(diphenylphosphine)ethane), and NiCl2(P(n-Bu)3)2. In some embodiments, the nickel catalyst is NiCl2(P(n-Bu)3)2.

[0030] In some embodiments, the alkali system comprises one or more inorganic bases. In some embodiments, the alkali system comprises K₂CO₃, Cs₂CO₃, Li₂CO₃, CsOH, KOH, or any combination thereof. In some embodiments, the alkali system comprises a mixture of K₂CO₃ and Cs₂CO₃.

[0031] In some embodiments, the reaction of the compound of formula (IV) with the borizing agent is carried out in a solvent system. In some embodiments, the solvent system comprises tetrahydrofuran (THF). In some embodiments, the solvent system comprises 2-methyl-tetrahydrofuran (MeTHF). In some embodiments, the solvent system comprises 1,4-dioxane. In some embodiments, the solvent system comprises methyl tert-butyl ether.

[0032] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from: Preferred

[0033] In some embodiments, the compound of formula (I-1) has the following structure:

[0034] In some embodiments, the compound of formula (I-3) has the following structure:

[0035] In some embodiments, the compound of formula (IV) has the following structure:

[0036] This disclosure provides an organoboron intermediate having the following structure:

[0037] R1 is a carboxylic acid protecting group. In some embodiments, R1 is C 1-6 alkyl.

[0038] In some implementations, the organoboron intermediate has the following structure:

[0039] This disclosure also provides chiral complex intermediates having the following structures: R1 is a carboxylic acid protecting group. In some embodiments, R1 is C 1-6 alkyl.

[0040] In some implementations, the structure of the chiral complex intermediate is as follows:

[0041] This disclosure also provides compounds with the following structures:

[0042] Another aspect of this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I) prepared according to the foregoing method or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0043] Terminology Explanation

[0044] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0045] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms are also included. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. Alkyl groups can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable junction, preferably one or more of the following groups, independently selected from halogens, hydroxyl, oxo, cyano, amino, C... 1-6 Alkyl, C 1- 6-alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0046] The term "alkenyl" refers to an unsaturated aliphatic straight-chain or branched hydrocarbon group containing one or more carbon-carbon double bonds. Exemplary alkenyl groups include C2-C8, C2-C7, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl groups. These include, but are not limited to, vinyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotonyl), etc. Alkenyl groups used in any context herein may optionally be substituted in the same manner as alkyl groups.

[0047] The term "alkynyl" refers to an unsaturated aliphatic straight-chain or branched hydrocarbon group containing one or more carbon-carbon triple bonds. Exemplary alkynyl groups include C2-C8, C2-C7, C2-C6, C2-C4, C3-C12, and C3-C6 alkynyl groups. These include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, pentynyl-4-alkynyl, and pentynyl-1,4-diynyl. In any context herein, the alkynyl group may optionally be substituted in the same manner as the alkyl group.

[0048] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. Cycloalkyl groups can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, independently selected from halogens, hydroxyl, oxo, cyano, amino, C... 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0049] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. Cycloalkyl groups can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, independently selected from halogens, hydroxyl, oxo, cyano, amino, C... 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0050] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m(where m is an integer from 0 to 2) heteroatoms, but excluding the -OO-, -OS-, or -SS- ring portions, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of "heterocyclic alkyl" include: etc.

[0051] The heterocyclic alkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocyclic alkyl ring, and non-limiting examples include:

[0052] wait.

[0053] Heterocyclic alkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, oxo groups, cyano groups, amino groups, and C4 groups. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with a halogen, hydroxyl, nitro, cyano, or amino group.

[0054] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, oxo groups, cyano groups, amino groups, and C- groups. 1-6 Alkyl, C 1- 6-alkoxy, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0055] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0056] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Alkyne group, 3- to 6-membered cycloalkoxy group, 3- to 6-membered heterocycloalkoxy group, C3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 The alkynyl group, 3 to 6 cycloalkoxy group, 3 to 6 heterocycloalkoxy group, 3 to 8 cycloalkenyl group, 5 to 6 aryl group, or heteroaryl group may be selected from one or more halogens, hydroxyl groups, cyano groups, amino groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl-substituted.

[0057] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrole, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazole, benzimidazolyl, etc. wait.

[0058] The heteroaryl ring may be fused to an aryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0059] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, cyano groups, amino groups, C4 groups, etc. 1-6 Alkyl or C 1-6 Alkyl group.

[0060] The term "heterocyclic group" refers to a ring composed of atoms other than carbon atoms, including heterocyclic alkyl groups and heteroaromatic rings.

[0061] The term "hydroxyl group" refers to the -OH group.

[0062] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0063] The term "cyano" refers to -CN.

[0064] The term "amino" refers to -NH2.

[0065] The term "nitro" refers to -NO2.

[0066] The term "oxo" refers to the =O substituent.

[0067] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. When the substituent is a ketone or an oxo (i.e., =O), two (2) hydrogen atoms on the atom are optionally substituted.

[0068] A "carboxylic acid protecting group" refers to a group that can be attached to the -C(O)O- moiety of a carboxylic acid to protect it from reaction and can be easily eliminated after the reaction. Suitable carboxylic acid protecting groups include, but are not limited to, C... 1-6 Alkyl, C 5-7 cycloalkyl, phenyl, phenyl C 1-6 Alkyl groups, etc.

[0069] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity. Detailed Implementation

[0070] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0071] Experimental methods not specifying specific conditions in the embodiments of this disclosure are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents not specifying their source are commercially available, conventional reagents.

[0072] NMR shift (δ) with 10 -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO) as the solvent. 6 ), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), deuterated acetonitrile (CD3CN), with tetramethylsilane (TMS) as the internal standard.

[0073] MS measurements were performed using a Shimadzu 2010 Mass Spectrometer or an Agilent 6110 AMSD mass spectrometer.

[0074] The LMCS was measured using an Agilent 6125B.

[0075] HPLC determinations were performed using a Shimadzu LC-20A system, Shimadzu LC-2010HT series, or Agilent 1200LC high-performance liquid chromatograph (Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column).

[0076] Chiral HPLC analysis was performed using Chiralpak IC-3 100×4.6mm ID, 3um, Chiralpak AD-3 150×4.6mm ID, 3um, Chiralpak AD-3 50×4.6mm ID, 3um, Chiralpak AS-3 150×4.6mm ID, 3um, Chiralpak AS-3 100×4.6mm ID, 3μm, ChiralCel OD-3 150×4.6mm ID, 3um, Chiralcel OD-3 100×4.6mm ID, 3μm, ChiralCel OJ-H 150×4.6mm ID, 5um, Chiralcel OJ-3 150×4.6mm ID, 3um chromatographic column; Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin layer chromatography. The silica gel plates used for thin layer chromatography (TLC) are 0.15mm to 0.2mm in diameter, and the diameter of the silica gel plates used for thin layer chromatography separation and purification is 0.4mm to 0.5mm.

[0077] Column chromatography typically uses Yantai Huanghai silica gel of 100-200 mesh, 200-300 mesh, or 300-400 mesh as the carrier.

[0078] Chiral preparation columns used were DAICL CHIRALPAK IC (250 mm * 30 mm, 10 μm) or Phenomenex-Amylose-1 (250 mm * 30 mm, 5 μm).

[0079] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0080] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0081] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, and D: petroleum ether / ethyl acetate / methanol. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0082] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, and D: petroleum ether / ethyl acetate / methanol. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0083] Example 1

[0084] Preparation of compound 1b in step one

[0085] DMSO (14 L) and NaOH (1.36 kg) were added to the reaction vessel, and 6-hydroxy-1,4-benzodioxane (3.54 kg, 22.6 mol) and 2-bromo-1,1-diethoxyethane (4.8 kg, 24.0 mol) were added while stirring. The temperature was raised to 50℃-60℃. After the reaction was completed, the reaction solution was concentrated, diluted with purified water, extracted with methyl tert-butyl ether, washed with purified water and saturated sodium chloride aqueous solution, concentrated and distilled with tetrahydrofuran to obtain 5.2 kg of crude product, namely compound 1b, with a purity of 98% and a yield of 91%, which was directly used in the next reaction.

[0086] 1 H NMR (400MHz, CDCl3) δ6.80(d,J=8.8Hz,1H),6.51(d,J=2.9Hz,1H),6.48(dd,J=8.8,2.9Hz,1H),4.84(t,J=5.2Hz,1H),4.26(tdd ,J=5.9,3.7,2.0Hz,4H),3.97(d,J=5.2Hz,2H),3.79(dq,J=9.3,7.1Hz,2H),3.66(dq,J=9.4,7.1Hz,2H),1.28(t,J=7.1Hz,6H).

[0087] Step 2: Preparation of compound 1c

[0088] Compound 1b (5.0 kg, 18.6 mol) and THF (50 L) were added to the reaction vessel. The temperature was lowered to -30 to -40 °C, and nBuLi (15 L, 2.5 M in Hex) and diethyl carbonate (6.6 kg) were added dropwise. After the addition was complete, the mixture was brought back to room temperature and stirred. After the reaction was complete, purified water was added to quench the reaction, and the mixture was extracted with methyl tert-butyl ether. The mixture was washed with purified water and saturated sodium chloride solution, and concentrated under reduced pressure to obtain 5.6 kg of crude product, namely compound 1c, with a yield of 90% and a purity of 76.5%. This crude product was directly added to the next reaction step.

[0089] 1 H NMR (400MHz, CDCl3) δ6.80(d,J=8.8Hz,1H),6.51(d,J=2.9Hz,1H),6.48(dd,J=8.8,2.9Hz,1H),4.84(t,J=5.2Hz,1H),4.26(tdd ,J=5.9,3.7,2.0Hz,4H),3.97(d,J=5.2Hz,2H),3.79(dq,J=9.3,7.1Hz,2H),3.66(dq,J=9.4,7.1Hz,2H),1.28(t,J=7.1Hz,6H).

[0090] Step 3: Preparation of Compound 1

[0091] Compound 1c (3 kg, 8.8 mol) was added to a reaction vessel and dissolved in 30 L of chlorobenzene. Phosphoric acid (6 kg, 6.1 mol) was then added, and the mixture was heated to 100-110 °C and stirred. After the reaction was complete, the mixture was extracted with dichloromethane, washed with purified water and a saturated sodium chloride solution, concentrated under reduced pressure, and then subjected to column chromatography to obtain 500 g of compound 1, with a yield of 30% and a purity of 90%.

[0092] 1 H NMR (400MHz, CDCl3) δ7.61(d,J=2.1Hz,1H),7.19(s,1H),6.67(d,J=2.1Hz,1H),4 .51(q,J=7.1Hz,2H),4.42–4.37(m,2H),4.34–4.29(m,2H),1.47(t,J=7.1Hz,3H).

[0093] Example 2

[0094] Step 4: Preparation of Compound 2

[0095] In a 2L three-necked flask, nickel chloride (80g, 0.6mol), EtOH (1L), and tri-n-butylphosphine (245g, 1.2mol) were added. The mixture was heated to 65-75℃ and stirred to prepare an ethanol solution of the nickel catalyst for later use. Compound 1 (1.0Kg, 4.0mol), cesium carbonate (2.63Kg, 8.0mol), potassium carbonate (0.56Kg, 4.0mol), B2(Pin)2 (1.53Kg, 6.0mol), and MeTHF (10L) were added to a 50L reactor. The mixture was stirred, heated to 30-40℃, and the prepared nickel catalyst ethanol solution was slowly added dropwise. The reaction was allowed to proceed for 1-2 hours. After the reaction was complete, water (7 L) was added, followed by slow addition of concentrated hydrochloric acid (2.5 L) to adjust the pH to less than 1. Then, n-heptane (7 L) was added, and the mixture was stirred to precipitate pinacol. The solution was filtered, and the filtrate was extracted with MeTHF, washed with 25% sodium chloride aqueous solution until pH ~6, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain 1.3 kg of crude product. The crude product was dissolved in ethyl acetate, and n-heptane was added dropwise to precipitate a solid. The mixture was stirred and filtered, and the filter cake was washed with n-heptane and dried under vacuum to obtain 990 g of a white solid with a purity of 98% and a yield of 89%, which is compound 2.

[0096] 1 H NMR (400MHz, DMSO) δ9.01 (s, 1H), 7.69 (d, J = 11.9Hz, 1H), 7.12 (s, 1H), 6.02 (d, J=11.9Hz,1H),4.36(q,J=7.1Hz,4H),4.31–4.25(m,2H),1.33(t,J=7.1Hz,3H).

[0097] Step 5: Preparation of Compound 3

[0098] Compound 2 (700 g, 2.53 mol), MeTHF (4.9 L), and (S)-(-)-2-phenylglycine (350 g, 2.53 mol) were added to a reaction vessel and stirred until a large amount of solid precipitated. Heptane was added dropwise, stirred, filtered, and the filter cake was washed with heptane and dried under vacuum to give 1.03 kg of a pale yellow solid, which was compound 3, with a yield of 91%.

[0099] 1H NMR (400MHz, DMSO) δ7.53–7.24(m,5H),6.79(d,J=12.2Hz,1H),6.65(s,1H),6.10(s,2H),5.76(d,J=11.5Hz,1H),4.97( d,J=72.0Hz,1H),4.20(d,J=18.5Hz,6H),3.34(d,J=52.0Hz,1H),2.60(d,J=58.0Hz,1H),1.29(dd,J=30.1,14.9Hz,3H).

[0100] Step 6: Preparation of Compound 4

[0101] Zn powder (1.0 kg, 15 mol) and CuCl (150 g, 1.5 mol) were added to MeTHF (10 L) and stirred at room temperature. Acetyl chloride (10 g) and CH2Br2 (220 g) were added dropwise, and the temperature was raised to 50-60 °C while stirring. Compound 3 (1.0 kg, 2.5 mol) was added, and the temperature inside the reactor was controlled at 65-75 °C. CH2Br2 (110 g) was added dropwise, and after the internal temperature rose significantly, the remaining CH2Br2 (2.31 kg) was slowly added dropwise. After the reaction was completed, the reaction temperature was lowered to 5-10 °C, and 15% wt ammonium chloride aqueous solution (5 L) was added dropwise. The mixture was extracted with MeTHF, washed with dilute hydrochloric acid aqueous solution, and the combined acid and aqueous phases were extracted with MeTHF. The mixture was washed with 25% saline solution until pH ~6, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, namely compound 4.

[0102] 1 H NMR (400MHz, DMSO) δ9.13 (s, 1H), 6.89 (s, 1H), 4.31–4.11 (m, 6H), 1.25 (t, J = 7.1Hz, 4H) ,1.12(d,J=6.0Hz,1H), 0.44(ddd,J=10.5,8.1,6.0Hz,1H), 0.24(dt,J=6.0,3.8Hz,1H).

[0103] Step 7: Preparation of compound 4-Na

[0104] Compound 4 (287 g, 0.99 mol, 1.0 eq) and MeTHF (1.7 L, 6 vol) were added to a three-necked flask, followed by an aqueous solution of NaOH (103 g, 3 eq. of NaOH and 2.3 L, 8 vol of purified water). The mixture was heated to 65-75 °C and stirred for 16-20 hours. After the reaction was completed, the temperature was lowered to 15-25 °C and the mixture was separated. The aqueous phase was washed once with MeTHF (1.4 L, 5 vol). Isopropanol (11.5 L, 40 vol) was added dropwise to the aqueous phase to precipitate a solid. After the reaction was completed, the mixture was stirred at 15-25 °C for 1 hour and then filtered. The filter cake was washed with isopropanol (570 mL, 2 vol). The wet product was dried at 45-55 °C for 8-12 hours to obtain 4-Na, with a yield of 95%.

[0105] 1 H NMR (400MHz, D2O) δ6.56(s,1H),4.10(s,4H),1.65–1.56(m,1H),0.72–0.63(m,1H),0.20(dt,J=6.2,3.1Hz,1H),0.09(td,J=9.3,6.7Hz,1H).

[0106] Example 3

[0107] Chiral auxiliaries were screened using Zn-Cu / CH2I2 conditions. The reaction conditions were as follows: Compound 2 (7 g, 25.3 mmol), MeTHF (50 mL), and the corresponding chiral auxiliaries Aux* (as shown in Table 1) were added to a reaction flask. The mixture was stirred until a large amount of solid precipitated, then n-heptane was added dropwise. The mixture was stirred, filtered, and dried under vacuum or concentrated to dryness to obtain the corresponding chiral complex Aux-2. Then, Zn-Cu (2.0 eq) and the corresponding chiral complex Aux-2 (1.0 eq) were added to MeTHF (10 v), the temperature was raised to 50-60 °C, CH2I2 (2.0 eq) was added dropwise, and the mixture was stirred at 50-60 °C for 2 hours. After the reaction was complete, samples of the reaction solution were taken to detect enantiomeric reactions. The results are shown in Table 1 below.

[0108] Table 1 shows the results of screening chiral auxiliaries using the Zn-Cu / CH2I2 condition.

[0109] *The ratio of target configuration to isomer is derived from the chiral chromatographic peak area integral ratio %:%

[0110] Example 4

[0111] Chiral auxiliaries were screened using the Zn / CuCl / CH2Br2 / AcCl reaction conditions. The reaction conditions were as follows: Compound 2 (7 g, 25.3 mmol), MeTHF (50 mL), and the corresponding chiral auxiliaries Aux* as shown in Table 2 were added to a reaction flask and stirred until a large amount of solid precipitated. Then, n-heptane was added dropwise, stirred, filtered, and dried under vacuum or directly concentrated to dryness to obtain the corresponding chiral auxiliary compound Aux-2. Zn powder (10 g, 15 mmol) and CuCl (1.5 g, 1.5 mmol) were added to MeTHF (100 mL), stirred at room temperature, and acetyl chloride (0.1 g, 0.05 eq) and CH2Br2 (2.2 g, 0.5 eq) were added dropwise. The temperature was raised to 50-60 °C, and stirred for 1-2 hours. Compound 3 (10 g, 2.5 mmol) was added, and the temperature inside the reaction vessel was controlled at 65-80℃. CH2Br2 (24.2 g, 5.5 eq.) was added dropwise. After the reaction was completed, the enantiomeric composition of the reaction solution was analyzed. The results are shown in Table 2 below:

[0112] Table 2 shows the results of screening chiral auxiliaries using the Zn / CuCl / CH2Br2 / AcCl conditions.

[0113] *The ratio of target configuration to isomer is derived from the chiral chromatographic peak area integral ratio %:%

[0114] Screening results for chiral auxiliaries showed that (S)-(-)-2-phenylglycine, (S,S)-(-)-2-amino-1,2-diphenylethanol, (S)-(+)-phenyl-1,2-ethylene glycol, (1S,2R)-2-amino-1,2-diphenylethanol, and (S)-(+)-2-phenylglycine all yielded an excess of the target configuration when used as chiral auxiliaries. Among them, (S)-(-)-2-phenylglycine and (S,S)-(-)-2-amino-1,2-diphenylethanol achieved a chiral purity of approximately 95% for the target configuration.

Claims

1. A process for preparing a compound represented by the formula (I-3) or a pharmaceutically acceptable salt thereof, The method comprises the following steps: Organoboron intermediates in combination with one or more chiral auxiliaries to form a chiral complex intermediate, the chiral auxiliaries being selected from the group consisting of (S)-(-)-2-phenylglycinol, (S,S)-(-)-2-amino-1,2-diphenylethanol, (S)-(+)-phenyl-1,2-ethanediol, (1S,2R)-2-amino-1,2-diphenylethanol, (S)-(+)-2-phenylglycinol; converting the chiral complex into a compound of formula (I-3), wherein: Y is independently selected from CH2, NH, O, S; R1 is a carboxylic acid protecting group; R2is OH or optionally substituted -O-C 1-6 alkyl; R c selected from the group consisting of optionally substituted C1-C6alkyl, halogen, deuterium, hydroxyl, thiol, -NR i R j , oxo, thioxo, -C(O)R k , -C(O)OR k , -S(O)R k , -S(O)OR k , -S(O)(O)R k , -S(O)(O)OR k , -C(S)R k , nitro, cyano, C1-C6alkoxy, C1-C6alkylsulfidyl, C2-C6alkenyl, C2-C6alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 7- to 10-membered fused cycloalkyl, 7- to 10-membered fused heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused aryl, 5- to 12-membered fused heteroaryl; n is selected from 1, 2, 3, 4, 5 or 6; m is selected from 0, 1, 2, 3, 4, 5 or 6.

2. The method according to claim 1, wherein the chiral auxiliaries are selected from the group consisting of (S)-(-)-2-phenylglycinol and / or (S,S)-(-)-2-amino-1,2-diphenylethanol.

3. The method according to claim 1 or 2, wherein the conversion of the chiral complex comprises reacting the chiral complex with a cyclopropanating agent.

4. The method according to claim 3, wherein the cyclopropanating agent comprises CH2I2 or CH2Br2, and one or more metal compounds.

5. The method according to claim 4, wherein the metal compounds are selected from the group consisting of Zn / Cu, Zn / Ag, ZnEt2, a mixture of Zn and CuCl, preferably Zn / Cu, a mixture of Zn and CuCl.

6. The method according to claim 4, wherein the cyclopropanating agent comprises CH2I2 and Zn / Cu.

7. The method according to claim 4, wherein the cyclopropanating agent comprises CH2Br2, Zn and CuCl.

8. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises the step of hydrolysing a compound of formula (I-3) ###00006### (I-3) to a compound of formula (I), ###00007### (I) 9. The method according to claim 8, wherein the hydrolysis step is performed under basic conditions, preferably the base is NaOH.

10. The method of claim 8, the compound of Formula (I) or pharmaceutically acceptable salt thereof is selected from preferably 11. The method of any one of claims 1-10, wherein the compound of Formula (I-1) has the structure: ###00006### (I-1).

12. The method of any one of claims 1-11, wherein the compound of Formula (I-3) has the structure: ###00010### (I-3).

13. An organoboron intermediate having the structure: ###00010### 10 wherein R1 is a carboxylic acid protecting group.

14. Chiral complex intermediates having the following structures: wherein, R1 is a carboxylic acid protecting group.

15. A compound having the structure:

Images