Hydroxamic acid compound or pharmaceutically acceptable salt thereof, and use thereof and preparation method therefor

Abstract

The present application relates to a compound as shown in the following formula (1) or a pharmaceutically acceptable salt thereof, wherein R is C1-6 alkyl. The present application also relates to the use of the compound or the pharmaceutically acceptable salt thereof for preparing a drug for resisting gram-negative bacteria, and a method for preparing the compound or the pharmaceutically acceptable salt thereof.

Description

Hydroxamic acid compound or its pharmaceutically acceptable salt, use and preparation method thereof Technical Field The present application relates to a novel hydroxamic acid compound or a pharmaceutically acceptable salt thereof, use of the compound or the pharmaceutically acceptable salt thereof for preparing an anti-Gram-negative bacteria drug, and a method for preparing the compound or the pharmaceutically acceptable salt thereof. Background Art Bacterial drug resistance is becoming increasingly serious, especially for Gram-negative bacteria. The number of deaths due to bacterial infections is increasing year by year, which seriously threatens human life and health. Although many antibacterial drugs have been developed, such as β-lactams, aminoglycosides, fluoroquinolones, glycopeptides, etc., they all have varying degrees of drug resistance or toxicity, which greatly limits their application. UDP-3-O(R-hydroxytetradecanoyl)-N-acetamidoglucose deacetylase (LpxC) is a key enzyme that catalyzes the synthesis of lipid A, the main component of lipopolysaccharide in the outer membrane of Gram-negative bacteria. The absence or overexpression of LpxC will kill some Gram-negative bacteria, making it an ideal target for anti-Gram-negative drugs. Although there have been many advances in this field, there is still a need for new LpxC inhibitors that not only have bactericidal activity against Gram-negative bacteria, but also have acceptable toxicity or tolerability. The prior art such as Chinese patent application CN10329878A discloses the LpxC inhibitor ACHN-975 with the following structure. The compound was developed by Achaogen and is a LpxC inhibitor that has entered Phase I clinical trials. However, due to some reasons, the compound ultimately failed to become a drug. Summary of the invention The present invention aims to provide novel LpxC inhibitors with better activity and lower toxicity. Specifically, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof: Wherein R is alkyl, cycloalkyl, aralkyl, preferably lower alkyl, more preferably C 1-6 alkyl. Another aspect of the present invention provides a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof: In another aspect, the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: In another aspect, the present invention provides a compound represented by any one of the following formulae (Ia) to (Id) or a pharmaceutically acceptable salt thereof: The present invention also relates to a pharmaceutical composition comprising the compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compound of formula (1) is preferably a compound of formula (2), more preferably a compound of formula (I), further preferably one or more selected from the group consisting of compounds (Ia), (Ib), (Ic) and (Ib), and particularly preferably a compound of formula (Ia). The present invention also relates to the use of the above-mentioned compound or its pharmaceutically acceptable salt for preparing an anti-Gram-negative bacteria drug. The Gram-negative bacteria include but are not limited to Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Citrobacter freundii, Pantoea agglomerans, Proteus vulgaris, Proteus mirabilis and Shigella flexneri. The present invention further relates to a method for preparing the compound represented by the above formula Ia, which method comprises any one or more of the following steps: The present invention further relates to a method for preparing the compound represented by the above formula Ib, Ic or Id, which comprises any one or more of the following steps, wherein Ib uses trans-2-butene-1,4-diol as a starting material, and formulas Ic and Id use cis-2-butene-1,4-diol as a starting material, and the cross bond in the formula represents cis-2-butene-1,4-diol. form or trans form. BRIEF DESCRIPTION OF THE DRAWINGS FIG1 is a circular dichroism spectrum of compound 8 in Example 1. FIG2 is a single crystal X-ray diffraction pattern of compound 8 in Example 1. FIG3 is a circular dichroism spectrum of compound 11 in Example 4. DETAILED DESCRIPTION In the compound represented by formula (1) or its pharmaceutically acceptable salt as described above in the present application, R is alkyl, cycloalkyl, aralkyl, preferably lower alkyl, more preferably C 1-6 Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc., and a methyl group is particularly preferred. Preferably, the compound represented by formula (1) is the compound represented by formula (2) described above in the present application. More preferably, the compound represented by formula (2) is the compound represented by formula (I) described above in the present application. The compounds of formula (1), (2) and (I) of the present application can be prepared by referring to the methods described in known documents such as CN101765585A and CN103298780A. In the present application, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid, and the acid can be selected from: trifluoroacetic acid, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, succinic acid, fumaric acid, acetic acid, lactic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, etc., but is not limited to these. In the compounds of formula (1), (2) and (I) of the present application, the three-membered ring contains two chiral carbon atoms, including four isomers, which are extremely difficult to prepare and separate and purify. The present invention prepares and separates the isomeric compounds represented by formula Ia, Ib, Ic and Id for the first time. The present invention uses 2-butene-1,4-diol as a starting material and prepares the corresponding optical isomers by constructing a three-membered ring chiral center from scratch. Formulas Ia and Ib use trans-2-butene-1,4-diol as a starting material, and formulas Ic and Id use cis-2-butene-1,4-diol as a starting material. Formula Ia is a one-step reaction to construct a chiral three-membered ring through an asymmetric Simmons-Smith cyclopropanation reaction; Formulas Ib, Ic, and Id are a four-step reaction through the split chiral auxiliary reagent D / L-(±)-diisopropyl tartrate Construct the chiral center of the three-membered ring. Specifically, the present application provides a method for preparing a compound represented by formula Ia, the method comprising: (1) subjecting trans-2-butene-1,4-diol to an esterification reaction with benzoyl chloride under alkaline conditions to obtain benzoyl mono-protected 2-butene-1,4-diol; (2) Benzoyl mono-protected 2-butene-1,4-diol was subjected to an asymmetric Simmons-Smith cyclopropanation reaction using an asymmetric inducing agent to obtain methyl ((1R,2R)-2-(hydroxymethyl)cyclopropyl)benzoate. (3) Methyl ((1R,2R)-2-(hydroxymethyl)cyclopropyl)benzoate was subjected to Dess-Martin oxidation, Corey-Fuchs reaction, debromination, Cadiot-Chodkiewicz reaction, hydrolysis, methylation, condensation with (S)-2-amino-3-(tert-butyloxycarbonylamino)-3-methylbutanoate, deprotection and hydroxylamination to give optical isomer Ia. In the asymmetric Simmons-Smith cyclopropanation reaction, the asymmetric inducer is preferably a chiral butyl borate or a chiral sulfonamide ligand, more preferably 2-butyl-N,N,N',N'-tetramethyl-dipentaborane-(4R,5R)-diformamide; the amount of the asymmetric inducer used relative to the raw material compound is 1.05 to 1.1 equivalents. In the Dess-Martin periodinane oxidation reaction, the molar ratio of the raw material compound to the Dess-Martin periodinane is preferably 1:(1.0-1.2), the temperature is preferably room temperature, and the oxidation reaction time is preferably 2-5 hours. In the Corey-Fuchs reaction, the reaction temperature is preferably -20 to -78°C. More specifically, the present application provides a method for preparing a compound represented by formula Ia, which method comprises any one or more of the following steps: Step 1 can be carried out as follows, but is not limited thereto. Dissolve compound 1 in an organic solvent, add a base at -5°C to -10°C, slowly drop benzoyl chloride, and stir at the same temperature. After the reaction is complete, separate and obtain compound 2 by column chromatography or the like. The amount of benzoyl chloride added is preferably 0.9 to 1.05 equivalents, thereby controlling side reactions and obtaining benzoyl mono-protected 2-butene-1,4-diol. Examples of the base used in the above step 1 include sodium hydride, potassium carbonate / dimethyltin dichloride, and the like, and sodium hydride is preferred. Examples of the organic solvent used in the reaction of step 1 include tetrahydrofuran, N,N-dimethylformamide, and chloroform. Step 2 is an asymmetric Simmons-Smith cyclopropanation reaction, which can be carried out as follows, but is not limited thereto. At -20°C to -25°C, diethyl zinc is dissolved in an organic solvent, ethylene glycol dimethyl ether is added, diiodomethane is slowly added dropwise, and then compound 2 and an asymmetric inducer are added, and stirred at room temperature until the raw material disappears. The reaction solution is quenched with an ammonium chloride solution, the reaction solution is extracted, the organic phase is combined, dried, and concentrated to obtain a residue, and compound 3 is separated by column chromatography and the like. The organic solvent used includes but is not limited to dichloromethane or n-hexane, and the asymmetric inducer includes but is not limited to chiral butyl borate or chiral sulfonamide ligand, preferably 2-butyl-N,N,N',N'-tetramethyl-diisopentaborane-(4R,5R)-diformamide. The molar ratio of compound 2 to diethyl zinc and diiodomethane can be 1:(3-5):(6-10). The asymmetric inducer is preferably 1.05-1.1 equivalents relative to compound 2. Step 3 can be carried out as follows, but is not limited thereto. Under ice bath, dissolve compound 3 in an organic solvent. Add Dess-Martin periodinane and stir at room temperature until the raw material disappears. Quench the reaction with sodium thiosulfate solution and sodium bicarbonate solution, extract the reaction solution, concentrate it, and separate it by column chromatography or other means to obtain compound 4. The molar ratio of compound 3 to Dess-Martin periodinane can be 1:(1.0-1.2), and the reaction time is preferably 2-5h. The organic solvent is preferably dichloromethane. Step 4 is a Corey-Fuchs reaction, which can be carried out as follows, but is not limited thereto. Dissolve carbon tetrabromide in dichloromethane at -10°C to -20°C, add triphenylphosphine dichloromethane solution dropwise, cool to -20°C to -78°C, add compound 4, and monitor until the reaction is complete. Warm to room temperature, remove the solvent by vacuum distillation, dissolve in 40% ethanol solution by volume, add n-hexane and stir vigorously, let stand to separate, repeat 2-3 times, combine the n-hexane phases, and concentrate under reduced pressure to obtain compound 5, which can be directly used in the next step without purification. The molar ratio of compound 4, triphenylphosphine and carbon tetrabromide can be, for example, 1:2:4. Step 5 is a debromination reaction of dibromoolefin, which can be carried out as follows, but is not limited thereto. Compound 5 is dissolved in an organic solvent, a base is added, and the reaction is refluxed until the raw material disappears. The mixture is concentrated under reduced pressure, and compound 6 is obtained by separation by column chromatography or the like. The organic solvent is preferably tetrahydrofuran or 1,4-dioxane. The base can be tetrabutylammonium fluoride or its trihydrate, etc. Step 6 is a Cadiot-Chodkiewicz reaction, which can be carried out as follows, but is not limited thereto. Under an ice bath, cuprous chloride is dissolved in an aqueous solution of an organic amine, hydroxylamine hydrochloride is added, and then methyl 4-ethynylbenzoate and compound 6 are added, and stirred at a temperature of 0°C to room temperature until the reaction is complete. The reaction solution is extracted, concentrated, and separated by column chromatography and the like to obtain compound 7. The molar ratio of compound 6 to cuprous chloride, organic amine, and hydroxylamine hydrochloride can be, for example, 1:0.5:(20-30):(0.7-1). The organic amine includes, but is not limited to, ethylamine, n-butylamine, etc., preferably n-butylamine. The mass concentration of the aqueous solution of the organic amine is preferably 30%. Step 7 is a hydrolysis reaction, which can be carried out as follows, but is not limited thereto. Compound 7 is dissolved in a mixed solution of tetrahydrofuran and methanol, an aqueous solution of alkali is added, and the mixture is stirred at room temperature until the raw material disappears. Dilute hydrochloric acid is adjusted to pH 1 to 2, a solid is precipitated, and compound 8 is obtained by suction filtration. The molar ratio of compound 7 to the alkali can be, for example, 1:(3 to 4), and the reaction time can be 2 to 4 hours. The alkali includes, but is not limited to, lithium hydroxide or sodium hydroxide, etc., preferably sodium hydroxide. Step 8 is a methylation reaction, which can be carried out as follows, but is not limited thereto. Under ice bath, compound 8 is dissolved in an organic solvent, a base is added, iodomethane is added after stirring, and monitoring is performed until the starting material disappears. Hydrogen is added Sodium hydroxide aqueous solution, monitor until the reaction is complete. Dilute hydrochloric acid is used to adjust the pH to 1-2, extract the reaction solution, and concentrate to obtain compound 9. The organic solvent includes but is not limited to tetrahydrofuran or N,N-dimethylformamide. The molar ratio of compound 8 to the base and iodomethane can be, for example, 1:(3-4):(3-4), and the base is preferably sodium hydride. Step 9 is a condensation reaction, which can be carried out as follows, but is not limited thereto. Compound 9, (S)-2-amino-3-(tert-butyloxycarbonylamino)-3-methylbutyric acid methyl ester, and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate are dissolved in an organic solvent, an organic base is added, and the mixture is stirred at room temperature until the raw materials disappear. The reaction solution is extracted, concentrated, and separated by column chromatography or the like to obtain compound 10. The organic solvent includes but is not limited to dichloromethane or N,N-dimethylformamide, and the organic base includes but is not limited to diisopropylethylamine or triethylamine. The molar ratio of compound 9 and (S)-2-amino-3-(tert-butyloxycarbonylamino)-3-methylbutyric acid methyl ester, organic base and 2-(7-oxidized benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate can be 1:(1.1-1.3):(2-4):(1.1-1.3), and the reaction time can be 3-8 hours. Step 10 is a deprotection reaction, which can be carried out as follows, but is not limited thereto. Compound 10 is dissolved in an organic solvent, an acid is added, and the mixture is stirred at room temperature until complete. The mixture is concentrated to obtain compound 11. The organic solvent includes but is not limited to tetrahydrofuran, dichloromethane, ether, ethyl acetate, chloroform, etc., and the acid includes but is not limited to hydrochloric acid or trifluoroacetic acid. Step 11 is a hydroxylamine reaction, which can be carried out as follows, but is not limited thereto. Compound 11 is dissolved in an organic solvent, an aqueous hydroxylamine solution is added, and the mixture is stirred at room temperature until the raw material disappears. Concentrate, separate and purify the residue to obtain compound Ia. The separation and purification of the residue can be separated and purified by reverse phase HPLC (conditions: chromatographic column XDB-C18 column (21.2 mm × 250 mm, 7 μm; mobile phase A: methanol, B: water (containing 0.1% TFA), gradient elution (0-40 min: A 10%-100%); column temperature 25°C; flow rate 8 mL / min; detection wavelength 280 nm), and then freeze-dried to obtain compound Ia. The organic solvent includes but is not limited to isopropanol, methanol, tetrahydrofuran, etc. The molar ratio of compound 11 to the hydroxylamine in the aqueous hydroxylamine solution can be 1:(18-22). The concentration of the aqueous hydroxylamine solution can be, for example, 50% by mass. More specifically, the present application provides a method for preparing the compound represented by formula Ia, which comprises the following steps. The conditions and operation methods of the above steps are as described above. More specifically, the present application provides a method for preparing the compound represented by formula Ia, which comprises the following steps. The compound of formula I can be prepared by using the cis-trans mixture of 2-butene-1,4-diol as the raw material, without using an asymmetric inducing agent in step 2, and by the same method as the preparation method of the compound of formula Ia. Using trans-2-butene-1,4-diol as raw material, no asymmetric inducing agent is used in step 2, and other The racemate of Formula Ia / Ib can be prepared by the same method as the preparation method of the compound of Formula Ia above. The present invention also provides a method for preparing the compounds of formula Ib, Ic and Id, which comprises: (1) subjecting 2-butene-1,4-diol to an esterification reaction with benzoyl chloride under alkaline conditions to obtain benzoyl mono-protected 2-butene-1,4-diol; (2) 2-butene-1,4-diol mono-protected with benzoyl is oxidized to obtain an α,β-unsaturated aldehyde, which is then reacted with triethyl orthoformate to form an acetal, which is then reacted with optically active D-(-)-diisopropyl tartrate or L-(+)-diisopropyl tartrate, and then subjected to a Simmons-Smith cyclopropanation reaction and hydrolysis to obtain a highly optically active cyclopropane compound 2-formylcyclopropyl methylene benzoate; (3) The corresponding optical isomer 2-formylcyclopropyl methylene benzoate was subjected to Corey-Fuchs reaction, debromination, Cadiot-Chodkiewicz reaction, hydrolysis, methylation, condensation with (S)-2-amino-3-(tert-butyloxycarbonylamino)-3-methylbutanoate, deprotection and hydroxylamination to give optical isomers Ib, Ic and Id. More specifically, the present invention provides a method for preparing the compound represented by the above formula Ib, Ic or Id, which method comprises any one or more of the following steps: Steps 1', 7', 8', 9', 10', 11', 12', 13', and 14' correspond to steps 1, 4, 5, 6, 7, 8, 9, 10, and 11 in the preparation of the compound of formula Ia, respectively, and can be operated in the same manner. Step 2' can be carried out as follows, but is not limited thereto. Under an ice bath, compound 2 is dissolved in an organic solvent, a Dess-Martin periodinane is added, and the mixture is stirred at room temperature until the starting material disappears. The reaction is quenched with a sodium thiosulfate solution and a sodium bicarbonate solution, the reaction solution is extracted, concentrated, and separated by column chromatography or the like to obtain compound 3. The molar ratio of compound 2 to the Dess-Martin periodinane is preferably 1:(1.0-1.2). The organic solvent is preferably dichloromethane. Step 3' can be carried out as follows, but is not limited thereto. Compound 3 is dissolved in an organic solvent, catalytic amounts of ammonium nitrate and triethyl orthoformate are added, and the mixture is stirred at room temperature until the raw materials disappear. The mixture is concentrated under reduced pressure, and compound 4 is obtained by separation by column chromatography or the like. The organic solvent includes but is not limited to anhydrous ethanol, anhydrous methanol, and the like. The molar ratio of compound 3 to triethyl orthoformate and ammonium nitrate can be 1:(1.5-2):0.05. Step 4' can be carried out as follows, but is not limited thereto. Compound 4 is dissolved in an organic solvent, diisopropyl tartrate of corresponding configuration and a catalyst are added, and stirred until the raw material disappears. Concentrate, and separate to obtain compound 5 by means of column chromatography or the like. Diisopropyl tartrate of corresponding configuration is L-(+)-diisopropyl tartrate or D-(-)-diisopropyl tartrate. The organic solvent is preferably toluene, and the catalyst is preferably pyridine p-toluenesulfonate. The stirring temperature can be, for example, 90°C. Step 5' is a Simmons-Smith cyclopropanation reaction, which can be carried out as follows, but is not limited thereto. At -15°C to -20°C, compound 5 is dissolved in an organic solvent, diethylzinc toluene solution is added dropwise, and then diiodomethane is slowly added dropwise, and stirred at room temperature until the raw material disappears. The reaction solution is quenched with ammonium chloride solution, the reaction solution is extracted, the organic phases are combined, dried, and concentrated to obtain a residue, which is separated by column chromatography and the like to obtain compound 6. The organic solvent used includes but is not limited to dichloromethane or n-hexane. The molar ratio of compound 5 to diethylzinc and diiodomethane can be 1:(3-5):(6-10). Step 6' can be carried out as follows, but is not limited thereto. Compound 6 is dissolved in an aqueous solution of acetic acid having a mass fraction of 70% to 85%, preferably 80%, and stirred until the raw material disappears. The mixture is cooled to room temperature, and a sodium bicarbonate solution is slowly added until no bubbles are generated, and the mixture is extracted, concentrated, and separated by column chromatography or the like to obtain compound 7. The stirring temperature can be, for example, 90°C. More specifically, the present invention provides a method for preparing the compound represented by the above formula Ib, Ic or Id, which comprises the following steps: The pharmaceutical composition of the present invention comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Preferably, the compound of formula (2) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are included, more preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are included, further preferably, the compound of formula (Ia), (Ib), (Ic) and (Ib) are included, and a pharmaceutically acceptable carrier is included, and particularly preferably, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are included. The content of the above-mentioned compound in the pharmaceutical composition of the present invention is preferably 0.0001-99% by mass, more preferably 0.001-50% by mass, and further preferably 0.01-10% by mass. Pharmaceutically acceptable carriers include various auxiliary materials conventionally used in medicines or preparations, such as stabilizers, preservatives, dispersants, excipients, etc. The pharmaceutical composition of the present invention can be made into various preparations suitable for the use of active ingredients, including but not limited to oral preparations, injections, patches, suppositories, etc. The present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt or the above-mentioned composition for preparing a drug for treating Gram-negative bacterial infectious diseases. Gram-negative bacteria include, for example, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Citrobacter freundii, Pantoea agglomerans, Proteus vulgaris, Proteus mirabilis, Shigella flexneri, etc. The above-mentioned compound or its pharmaceutically acceptable salt of the present invention can be used in combination with other antibacterial agents or active ingredients. The combined use includes preparing a composition with other antibacterial agents or active ingredients, or administering them independently with other antibacterial agents or active ingredients simultaneously or at intervals. The present invention is further described in detail below in conjunction with the embodiments, but they should not be understood as limiting the scope of protection of the present invention. Any modifications and changes that do not deviate from the gist of the present invention fall within the scope of protection of the present invention. Unless otherwise specified, the reagents used in the following examples were commercially available. Example 1 Synthesis of N-(S)-3-amino-1-hydroxyamino-3-methyl-1-oxobutane-2-yl-4-[[(1R,2R)-2-(methoxymethylene)cyclopropyl]buta-1,3-diynyl]benzamide (Ia) (E)-4-Hydroxybutyl-2-enylbenzoate (Compound 2) -10 ℃, add 60% sodium hydride (90.80g, 2.27mol) in batches to a THF (1.50L) ​​solution of compound 1 (200.00g, 2.27mol), gas is generated, the temperature rises, and the addition rate is controlled to keep the internal temperature below 0 ℃. After the addition is completed, stir and react for 30min at the same temperature. The solution is gray and turbid, and is particularly viscous when the amount is large. Add benzoyl chloride (319.10g, 2.27mol) dropwise, control the internal temperature <0 ℃, after the addition is completed, warm to room temperature and stir to react for 3 hours. Add an appropriate amount of water to quench the reaction, filter to remove the sodium hydride mineral oil, wash the filter cake with THF, and concentrate the obtained filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography [eluent: petroleum ether: ethyl acetate (5:1-2:1)] to obtain a light yellow oil (compound 2) (227.00g, 52.1%). 1 H NMR (600 MHz, CDCl 3): δ:8.04(dd,J=8.2,1.5Hz,2H),7.56-7.52(m,1H),7.42(t,J=7.8Hz,2H),6.03-5.97( m,1H),5.95-5.90(m,1H),4.83-4.80(m,2H),4.18(dd,J=5.0,1.5Hz,2H),2.13(s,1H). MS-ESI(m / z):215[M+Na] + . Methyl ((1R,2R)-2-(Hydroxymethyl)cyclopropyl)benzoate (Compound 3) At -15℃, under argon protection, add ethylene glycol dimethyl ether (CAS: 110-71-4; 30.52g, 0.339mol) to dichloromethane (300mL), and stir at the same temperature for 5min. Add diethylzinc (1M n-hexane solution, 340mL, 0.339mol) in batches, and white smoke disappears above the liquid surface. After the addition is completed, stir at the same temperature for 10min. Under vigorous stirring, add diiodomethane (182.13g, 0.68mol) drop by drop, and the temperature rises significantly. Control the dropping speed to keep the internal temperature between -15℃ and -10℃. After the addition is completed, stir at the same temperature for 30min. Add a dichloromethane (100 mL) solution of 2-butyl-1,3,2-dioxaborolane-4S,5S-dicarboxylic acid bis(dimethylamide) (CAS: 161344-84-9; 20.26 g, 0.075 mol), and then immediately add a dichloromethane (90 mL) solution of compound 2 (13.00 g, 0.068 mol). After addition, stir at the same temperature for 30 minutes. Turn off the refrigeration, slowly warm to room temperature, and stir at room temperature (28°C) for 8 hours to complete the reaction. Transfer the reaction solution to a 2L single-mouth bottle and place it in a 0°C low-temperature reaction bath and stir for 10 minutes. Add saturated ammonium chloride aqueous solution (300 mL) in batches to quench the reaction. The temperature rises significantly. After addition, stir for 10 minutes. Transfer to a separatory funnel, extract the aqueous layer with dichloromethane (300 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a yellow oil. Add a mixed solution of ether (300 mL) and water (200 mL), stir the two-phase solution vigorously at room temperature for 1 hour, transfer to a separatory funnel, let stand and separate the layers, extract the aqueous layer with ether (200 mL × 2), combine the organic phases, and concentrate under reduced pressure to obtain about 250 mL of ether solution. The aqueous layer is used to recover the asymmetric inducer. At 0°C, add NaOH aqueous solution (2N, 270 mL) and 30% H 2 O 2The mixed solution of (45mL) was stirred for 10min, and the layers were separated and the organic phase was washed with 10% HCl aqueous solution (220mL), saturated sodium sulfite aqueous solution (220mL), saturated sodium bicarbonate aqueous solution (220mL) and saturated sodium chloride aqueous solution (220mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oil (compound 3) (13.32g, 95.1%), which was directly reacted in the next step without further purification. A small amount of the crude product was separated and purified by silica gel column chromatography [eluent: petroleum ether: ethyl acetate (3:1)] to obtain a colorless oil to determine the structure. Chiral HPLC purity: ee value is 81.1%, chiral HPLC conditions: chromatographic column: dacel ID (ID00CE-VA036) (4.6 mm × 250 mm, 5 μm); mobile phase A: methanol, B: water, gradient elution (0-10 min: A 20%-100%); column temperature 25 ° C; flow rate 1 mL / min; detection wavelength 254 nm]; specific rotation (c=1.00,CH 3 OH). 1 H NMR (600 MHz, CDCl 3 ): δ8.07-8.03(m,2H),7.55(tt,J=7.2,1.4Hz,1H),7.46-7.42(m,2H),4.25-4.16(m,2H),3.54(d d, J=11.4, 6.3Hz, 1H), 3.49 (dd, J=11.4, 6.7Hz, 1H), 1.67 (s, 2H), 1.23-1.17 (m, 2H), 0.66 (m, 2H). 13 C NMR (126 MHz, CDCl 3 ): δ166.81,132.99,130.36,129.63,128.41,68.30,65.92,19.90,15.75,8.59. MS-ESI(m / z):229[M+Na] + . Methyl ((1R,2R)-2-Formylcyclopropyl)benzoate (Compound 4) At -10°C, add Dess-Martin oxidant (50.91 g, 120 mmol) in batches to a solution of compound 3 (16.50 g, 80 mmol) in dichloromethane (300 mL). The temperature rises significantly, and the addition rate is controlled to keep the internal temperature between -7°C and -10°C. After the addition is completed and the temperature is stabilized, move to room temperature and stir for 3 hours. Filter by suction, wash the filter cake with dichloromethane, and neutralize the filtrate with saturated sodium bicarbonate solution to neutrality, extract and wash with saturated sodium thiosulfate aqueous solution (100 mL×2) and saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 30:1~10:1~5:1) to obtain a light yellow oil (compound 4) (13.31 g, 81.5%). 1 H NMR (600 MHz, CDCl 3 ): δ9.18(d,J=4.5Hz,1H),8.04-7.99(m,2H),7.57-7.53(m,1H),7.47-7.38(m,2H),4.36- 4.32(m,1H),4.22-4.17(m,1H),2.03-1.96(m,2H),1.42-1.38(m,1H),1.20-1.16(m,1H). 13 C NMR (151 MHz, CDCl 3 ): δ199.67,166.27,133.07,129.76,129.54,128.33,65.73,28.01,20.54,12.65. MS-APCI(m / z):205[M+H] + . Methyl ((1R,2R)-2-(2,2-dibromovinyl)cyclopropyl)benzoate (Compound 5) Under -20°C and argon protection, a solution of triphenylphosphine (68.40 g, 261 mmol) in DCM (75 mL) was added dropwise to a solution of carbon tetrabromide (43.24 g, 130 mmol) in DCM (60 mL) (the two colorless solutions turned into yellow liquids), and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to -78°C, and a solution of compound 4 (13.31 g, 65 mmol) in DCM (60 mL) was added dropwise, and the mixture was stirred at the same temperature for reaction. After 30 minutes, the mixture was naturally warmed to room temperature and stirred for 40 minutes. The solvent was evaporated under reduced pressure, dissolved in 40% ethanol solution (400 mL) to obtain a yellow liquid, and n-hexane was added and stirred vigorously for 10 minutes. The mixture was allowed to stand for stratification, and the mixture was repeated twice. The n-hexane layer was concentrated under reduced pressure, filtered, and the filter cake was washed with n-hexane. The yellow liquid was concentrated and separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 150:1) to obtain a light yellow solid (compound 5) (10.1 g, 43.0%). 1 H NMR (600 MHz, CDCl 3 ): δ8.08-8.04(m,2H),7.59-7.54(m,1H),7.47-7.42(m,2H),5.88(d,J=9.0Hz,1H),4.27(dd,J=11.6,6.9Hz,1H),4.19( dd,J=11.6,7.3Hz,1H),1.76-1.70(m,1H),1.51-1.44(m,1H),0.99(dt,J=8.6,5.4Hz,1H),0.87(dt,J=8.6,5.2Hz,1H). 13 C NMR (151 MHz, CDCl 3 ): δ166.47,139.84,132.95,130.17,129.61,128.34,87.09,67.26,21.16,19.22,12.12. MS-ESI(m / z):381[M+Na] + . Methyl ((1R,2R)-2-(2-bromoethynyl)cyclopropyl)benzoate (Compound 6) Compound 5 (10.10 g, 28 mmol) was dissolved in 250 mL of tetrahydrofuran, and tetrabutylammonium fluoride trihydrate (47.89 g, 152 mmol, the amount added must be greater than 3.0 eq) was added to form a brown solution, and stirred at 70°C for 5 h. The reaction solution was concentrated, 200 mL of ethyl acetate was added, washed with water, washed with saturated sodium chloride solution, concentrated, and purified by column separation (eluent: petroleum ether: ethyl acetate = 20:1) to obtain yellow oily compound 6 (5.57 g, 71.1%). Methyl 4-(((1R,2R)-2-((Benzoyloxy)methyl)cyclopropyl)buta-1,3-diynyl)benzoate (Compound 7) Under ice bath, add cuprous chloride (0.83 g, 8.34 mmol) to a 30% aqueous solution of n-butylamine (24.40 g, 333.6 mmol) to form a dark blue solution; add hydroxylamine hydrochloride (0.81 g, 11.68 mmol), the blue color fades and turns into a light yellow solution; add a tetrahydrofuran solution of methyl 4-ethynylbenzoate (2.67 g, 17 mmol), solid precipitates, then immediately add a tetrahydrofuran solution of compound 6 (5.57 g, 20 mmol), yellow turbid liquid, stir at room temperature overnight. Filter by suction, rinse the filter cake with ethyl acetate, mix the sample, separate and purify by column separation (eluent: petroleum ether: ethyl acetate = 100:1-50:1-30:1) to obtain a yellow oil (compound 7) (2.87 g, 48.0%). 1 H NMR (600 MHz, CDCl 3 ): δ8.08-8.02(m,2H),7.96(d,J=8.5Hz,2H),7.60-7.54(m,1H),7.52-7.49(m,2H),7.45(t,J=7.8Hz,2H),4.32-4.22(m,1H),4 .17-4.08(m,1H),3.91(s,3H),1.80-1.74(m,1H),1.57-4.52(m,1H),1.18-1.14(m,1H),1.08-1.00(m,1H),0.98-0.85(m,1H). 13 C NMR (151 MHz, CDCl 3 ): δ166.42,166.32,133.11,132.42,129.67,129.46,128.41,87.19,73. 87,66.76,66.59,61.47,52.26,21.65,21.22,14.09,13.73,6.59,6.27. MS-ESI(m / z):381[M+H] + . 4-[[(1R,2R)-2-(Hydroxymethyl)cyclopropyl]buta-1,3-diynyl]benzoic acid (Compound 8) Aqueous solution (10 mL) of sodium hydroxide (1.28 g, 32 mmol) was added to a solution of compound 7 (2.87 g, 8 mmol) in THF / MeOH (10 / 10 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, water (50 mL) was added to the concentrate, and the mixture was extracted with dichloromethane twice (20 mL×2). The aqueous phase was adjusted to about pH 2.0 with 1 mol / L hydrochloric acid, and then extracted with ethyl acetate (50 mL×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an off-white solid (compound 8) (1.54 g, 80.2%), which was directly used in the next step without purification. Compound 8 purity 99.51%, retention time 9.183min [HPLC conditions: chromatographic column SB-C 18 Column (4.6mm×150mm, 5μm; mobile phase A: methanol (containing 1‰ TFA), B: water (containing 1‰ TFA), gradient elution (0-10min: A20%-100%); column temperature 25°C; flow rate 1mL / min; detection wavelength 280nm]. Chiral HPLC purity: main peak retention time 7.697min, content 98.05%; isomer 1 retention time 6.255min, content 0.40%; isomer 2 retention time 6.506min, content 0.99% [Chiral HPLC conditions: chromatographic column Daicel ID (ID00CE-VA036) (4.6mm×250mm, 5μm); mobile phase A: ethanol (containing 1‰ TFA), B: n-hexane (containing 1‰ TFA), gradient elution (0-10min: A20%-100%); column temperature 25℃; flow rate 1mL / min; detection wavelength 280nm], ee value 99.2%. Specific rotation (c0.453, CH 3 OH)], Optical rotation determination method: accurately weigh the compound, place it in a 10mL volumetric flask, add analytical grade methanol to dissolve, quantify to 10mL scale, and measure it on a Rudolf polarimeter, using the corresponding blank solvent as blank. mp 181.4-183.6℃. 1 H NMR (600 MHz, DMSO-d 6 ): δ: 7.93(dd,J=16.8,7.7Hz,2H), 7.62(d,J=7.7Hz,2H), 7.50(t,J=7.5Hz,1H), 2.02-1.96(m,1H),1.48-1.44(m,1H),1.23(d,J=6.3Hz,3H),1.03-0.78(m,2H). MS-ESI(m / z):239[MH] - . In order to determine the absolute configuration of the constructed chiral three-membered ring, compound 8 was first subjected to an esterification reaction in sulfuric acid and methanol to obtain compound 8-1 to remove the influence of the carboxylic acid hydrogen bond on the dominant conformation in solution; then a similar chromophore 1,3-dienylphenyl was introduced at the hydroxyl group through a condensation reaction to obtain compound 8-2, which theoretically produced a negative chirality. Its actual chirality was determined by circular dichroism. Circular dichroism (ECCD) was performed using a JASCO J-815 circular dichroism spectrometer made in Japan. The spectrum from 200 to 450 nm was measured at room temperature. The concentration of the sample was 0.133% (w / v, methanol). The sample cup light diameter was 1 mm, the bandwidth was 2.00 nm, and the scanning speed was 100 nm / min. The ECCD results (shown in FIG1 ) were consistent with the chirality generated by the theory. In addition, 30 mg of compound 8 was dissolved in 50 ml of dichloromethane and allowed to evaporate naturally at 0°C to 10°C to obtain a single crystal of compound 8. Single crystal X-ray diffractometer analysis showed that the single crystal existed as a dimer due to the strong hydrogen bonding of the carboxyl group. The single crystal results (as shown in Figure 2) indicated that the cyclopropyl group was in R,R configuration, which was consistent with the circular dichroism results, thereby determining the absolute configuration of the two chiral centers on the three-membered ring. 4-(((1R,2R)-2-(methoxymethylene)cyclopropyl)buta-1,3-diynyl)benzoic acid (Compound 9) Under ice bath, 60% sodium hydride (1.26 g, 31.5 mmol) was added in batches to a DMF (20 mL) solution of compound 8 (2.52 g 10.5 mmol), stirred at the same temperature for 40 min, iodomethane (7.45 g, 52.5 mmol) was slowly added dropwise to the reaction solution, and after the temperature stabilized, the mixture was removed from the ice bath and stirred at room temperature in the dark for 10 h. Under ice bath, saturated ammonium chloride aqueous solution was added dropwise to quench the reaction, and ethyl acetate was added. (200 mL), washed with water (120 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2.61 g of a yellow oily liquid, with a yield of 97.7%, MS-ESI (m / z): 269 [M+H] + Without further purification, the next step reaction was carried out directly. A solution of sodium hydroxide (1.16 g, 29.1 mmol) in water (6 mL) was added to a solution of the yellow oil (2.61 g, 9.7 mmol) in THF / MeOH (6 mL / 6 mL) and the mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure, water (5 mL) was added to the concentrate, the pH was adjusted to about 3.0 with 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL×4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid compound 9 (2.03 g, 82.5%), MS-ESI (m / z): 253 [MH] - ; It was used directly in the next reaction without purification. (S)-2-[4-[[(1R,2R)-2-(methoxymethylene)cyclopropyl]buta-1,3-diynyl]benzamido]-3-(tert-butyloxycarbonylamino)-3-methylbutanoic acid methyl ester (Compound 10) (S)-2-amino-3-(tert-butyloxycarbonylamino)-3-methylbutyric acid methyl ester (1.43 g, 5.81 mmol, purchased from Bidex Pharmaceuticals, purity: 95%) and diisopropylethylamine (DIPEA, 1.50 g, 11.62 mmol) were added to a DCM (15 mL) solution of compound 9 (1.48 g, 5.81 mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 2.65 g, 6.97 mmol), and the mixture was stirred at room temperature for 4 h. The reaction solution was washed with water twice, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The product was separated and purified by silica gel column chromatography [eluent: petroleum ether: ethyl acetate = 10:1 to 1:1)] to obtain a yellow oil (compound 10) (2.70 g, 96.4%). (S)-3-Amino-2-[4-[[(1R,2R)-2-(methoxymethylene)cyclopropyl]buta-1,3-diynyl]benzamido]-3-methylbutanoic acid methyl ester hydrochloride (Compound 11) Compound 10 (2.70 g, 5.60 mmol) was dissolved in dichloromethane (20 mL), and 7 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. The pH was adjusted to 8 with 2N sodium hydroxide solution, and the organic phase was washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude yellow oil (compound 11) (2.16 g, 101%), which was used directly in the next step without purification. N-(S)-3-amino-1-hydroxyamino-3-methyl-1-oxobutan-2-yl-4-[[(1R,2R)-2-(methoxymethylene)cyclopropyl]buta-1,3-diynyl]benzamide (Compound Ia) Under ice bath, compound 11 (2.16 g, 5.65 mmol) was dissolved in isopropanol (20 mL), 50 mass% hydroxylamine aqueous solution (11.3 mL) was added, and the reaction was stirred at room temperature for 24 hours. The product was separated and purified by preparative liquid phase separation [mobile phase A: methanol, B: water, gradient elution (0-20 min: A 10%-100%; 25 min: A 100%; 26 min: A 10%; 30 min: A 10%); column temperature 25 ° C; flow rate 8 mL / min; detection wavelength 280 nm], concentrated and dried to obtain an off-white solid (compound Ia) (0.92 g, 42.6%). 1 H NMR (400 MHz, DMSO-d 6 ): δ11.23(s,1H),9.21(s,1H),8.82(d,J=9.3Hz,1H),8.31(s,3H),8.03( d,J=8.4Hz,2H),7.61(d,J=8.4Hz,2H),4.67(d,J=9.2Hz,1H),3.33(dd,J =10.6,5.4Hz,1H),3.24(s,3H),3.15(dd,J=10.7,6.6Hz,1H),1.58-1.45 (m,2H),1.36(s,3H),1.33(s,3H),1.05-0.97(m,1H),0.95-0.84(m,1H). 13 C NMR (126 MHz, DMSO-d 6 ): δ166.88,165.54,134.56,132.18,127.80,123.65,88.68,76.23,73.6 7,73.25,60.47,58.36,57.62,51.82,28.41,27.20,22.25,13.34,5.18. Preparation of trifluoroacetate of compound Ia: Compound Ia (2.17 g, 5.66 mmol) was dissolved in methanol (20 mL), cooled to -10°C, 1 mL of trifluoroacetic acid was added dropwise to generate white smoke, and stirred at the same temperature for 2 h. The mixture was concentrated under reduced pressure, and purified by preparative liquid phase separation [mobile phase A: methanol, B: water, gradient elution (0-20 min: A 10%-100%; 25 min: A 100%; 26 min: A 10%; 30 min: A 10%); column temperature 25°C; flow rate 8 mL / min; detection wavelength 280 nm], concentrated, and dried to obtain a light yellow solid (trifluoroacetate of compound Ia) (1.76 g, 63%). Preparation of Compound Ia hydrochloride: Compound Ia was dissolved in methanol, cooled to -5°C, dry hydrogen chloride gas was introduced into the solution for 30 min, and then stirred at the same temperature for 1 h. The solution was concentrated under reduced pressure, and purified by preparative liquid separation [mobile phase A: methanol, B: water, gradient elution (0-20 min: A 10%-100%; 25 min: A 100%; 26 min: A 10%; 30 min: A 10%); column temperature 25°C; flow rate 8 mL / min; detection wavelength 280 nm], concentrated, and dried to obtain a light yellow solid (Compound Ia hydrochloride). Example 2 Synthesis of N-(S)-3-amino-1-hydroxyamino-3-methyl-1-oxobutane-2-yl-4-[[(1S,2S)-2-(methoxymethylene)cyclopropyl]buta-1,3-diynyl]benzamide (Compound Ib) (E)-4-Hydroxybutyl-2-enylbenzoate (Compound 2) -10 ℃, add 60% sodium hydride (90.80g, 2.27mol) in batches to a THF (1.50L) ​​solution of compound 1 (200.00g, 2.27mol), gas is generated, the temperature rises, and the addition rate is controlled to keep the internal temperature below 0 ℃. After the addition is completed, stir and react for 30min at the same temperature. The solution is gray and turbid, and is particularly viscous when the amount is large. Add benzoyl chloride (319.10g, 2.27mol) dropwise, control the internal temperature <0 ℃, after the addition is completed, warm to room temperature and stir to react for 3 hours. Add an appropriate amount of water to quench the reaction, filter to remove the sodium hydride mineral oil, wash the filter cake with THF, and concentrate the obtained filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography [eluent: petroleum ether: ethyl acetate (5:1-2:1)] to obtain a light yellow oil (compound 2) (227.00g, 52.1%). (E)-4-Oxobutyl-2-enylbenzoate (Compound 3) At 0°C, DMP (25.02 g, 59.0 mmol) was added in batches to a solution of compound 2 (10.30 g, 53.6 mmol) in dichloromethane (DCM, 100 mL), and the internal temperature was controlled at -5°C to 0°C. After the addition, the mixture was stirred at room temperature for 4 hours. Saturated sodium thiosulfate solution and saturated sodium bicarbonate solution were slowly added, and the reaction was quenched by stirring for 30 min to precipitate a solid. The filtrate was filtered and allowed to stand for stratification. The aqueous layer was extracted with dichloromethane (100 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, a light yellow oil (compound 3) (11.60 g, >100%). (E)-4,4-diethoxybutyl-2-enylbenzoate (Compound 4) Ammonium nitrate (0.21 g, 2.63 mmol) was added to a solution of compound 3 (11.60 g, 61.1 mmol) and triethyl orthoformate (11.90 g, 80.4 mmol) in ethanol (50 mL), stirred at room temperature for 15 hours, and the reaction solution changed from light yellow to brown. The solvent was removed under reduced pressure, and the concentrate was dissolved in ethyl acetate (150 mL), washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride in sequence, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brown oil, which was separated and purified by silica gel column chromatography [eluent: petroleum ether: ethyl acetate (5:1)] to obtain a colorless oil (compound 4) (13.17 g, 85%). (4S,5S,E)-2-(3-Benzoyloxyprop-1-enyl)-1,3-dioxolane-4,5-dicarboxylic acid diisopropyl ester (Compound 5) Pyridinium p-toluenesulfonate (PPTS, 0.47 g, 1.9 mmol) was added to a toluene (50 mL) solution of compound 4 (9.89 g, 37.4 mmol) and D-(-)-diisopropyl tartarate (9.65 g, 41.2 mol, J&K Technology, 99%), and the mixture was heated to 90°C for 10 hours (byproduct ethanol was distilled off under reduced pressure). The reaction solution gradually changed from light yellow to brown. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography [eluent: petroleum ether: ethyl acetate (50:1-20:1)] to obtain a light yellow oil (compound 5) (9.86 g, 65%). (4S,5S)-2-[(1S,2S)-2-(Benzoyloxymethyl)cyclopropyl]-1,3-dioxolane-4,5-dicarboxylic acid diisopropyl ester (Compound 6) At -20°C, under argon protection, 2 mol / L diethylzinc toluene solution (37 mL, 72.8 mmol) was added in batches to a solution of compound 5 (9.86 g, 24.3 mmol) in n-hexane / dichloromethane (100 / 50 mL). After the addition was completed, diiodomethane (38.99 g, 145.6 mmol) was added dropwise while stirring vigorously. After the addition was completed, the mixture was heated to room temperature and stirred for 8 hours. A cold saturated aqueous ammonium chloride solution (200 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (100 mL×2). The organic phases were combined, washed with saturated sodium thiosulfate solution, water and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a light yellow oil (compound 6) (18.60 g, >100%). LCMS:

[0421] + [(1R,2R)-2-Formylcyclopropyl]methyl acetate (Compound 7) Compound 6 (18.60 g, 44.2 mmol) was dissolved in 80% acetic acid aqueous solution (60 mL), heated to 90°C and stirred for 5 hours. After cooling to room temperature, the reaction solution was dropped into a saturated sodium bicarbonate solution. The mixture was extracted with DCM (80 mL × 3), and the combined organic phase was washed with water and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent P / E = 10 / 1-5 / 1) to obtain a yellow oil (Compound 7) (2.28 g, 25%). [(1S,2S)-2-(2,2-Dibromovinyl)cyclopropyl]methylbenzoate (Compound 8) -20 ℃, under argon protection, a solution of triphenylphosphine (11.73g, 44.7mmol) in DCM (30mL) was added dropwise to a solution of carbon tetrabromide (7.41g, 22.4mmol) in DCM (20mL) (the two colorless solutions turned into yellow liquids), and the mixture was stirred and reacted at the same temperature for 30min. The mixture was cooled to -78 ℃, and a solution of compound 7 (2.28g, 11.2mmol) in DCM (10mL) was added dropwise, and the mixture was stirred and reacted at the same temperature for 30min (the yellow solution turned into a pink solution). The mixture was gradually warmed to room temperature, and the solvent was evaporated under reduced pressure to obtain a crude product. 200mL of 40% ethanol solution was added, and the mixture was extracted with n-hexane (80mL×3), and the organic phases were combined, washed with water, washed with saturated sodium chloride, and concentrated. A small amount of n-hexane remained, and the mixture was filtered with suction, and the filter cake was rinsed with ice n-hexane. The filtrate was concentrated to obtain a light yellow oil (compound 8) (3.50g, 87%). The subsequent preparation method is the same as the corresponding steps in Example 1 to obtain isomer Ib. LCMS-ESI(m / z):384.1[M+H] + . 1 H NMR (500 MHz, DMSO-d 6 ): δ8.16(s,1H),7.88(d,J=8.0Hz,2H),7.63(d,J=8.0Hz,2H),4.31(s,1H),3.35(dd,J=10.6,5.4Hz,1H),3 .26(s,3H),3.17(dd,J=10.6,6.6Hz,1H),1.59-1.50(m,2H),1.11(s,3H),1.03(s,4H),0.95-0.89(m,1H). Among them, 4-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)butane-1,3-diynyl)benzoic acid (Compound 11) has an ee value of 98.4% and a specific rotation of (c 0.401, CH3 OH)], determination method: accurately weigh the compound, place it in a 10mL volumetric flask, add analytical grade methanol to dissolve, quantify to 10mL scale, and measure it on a Rudolf polarimeter, using the corresponding blank solvent as blank. Simmons-Smith cyclopropanation reaction is CH 2 I 2 With Et 2 After Zn obtains a carbene-like compound, it forms a three-membered ring butterfly-shaped intermediate transition state with the olefin, which is carried out according to a synergistic mechanism. Therefore, in the absence of a chiral auxiliary, the trans or cis olefin, after the Simmons-Smith cyclopropanation reaction, each obtains two configurations of cyclopropane, and they are enantiomers of each other. Therefore, compound 8 in Example 1 and compound 11 in Example 2 are both synthesized from (E)-1,4-butenediol via a chiral auxiliary. The absolute configuration of compound 8 is confirmed to be (1R, 2R). Compound 11 and compound 8 are enantiomers of each other, with opposite signs and numbers. If the specific rotation is of similar value, its configuration is (1S,2S). Example 3 Synthesis of N-(S)-3-amino-1-hydroxyamino-3-methyl-1-oxobutane-2-yl-4-[[(1R,2S)-2-(methoxymethylene)cyclopropyl]buta-1,3-diynyl]benzamide (Compound Ic) The preparation method is the same as that of Example 2, except that cis-2-butene-1,4-diol is used as the raw material instead of trans-2-butene-1,4-diol, and the chemical resolution chiral reagent is L-(+)-diisopropyl tartarate. The purity of compound Ic is 98%. LCMS-ESI(m / z):384.3[M+H] + . 1 H NMR (500 MHz, DMSO-d 6 ): δ8.12(s,1H),7.85(d,J=8.0Hz,2H),7.61(d,J=8.0Hz,2H),4.28(s,1H),3.34(dd,J=10.6,5.4Hz,1H),3 .24(s,3H),3.15(dd,J=10.7,6.6Hz,1H),1.57-1.48(m,2H),1.09(s,3H),1.01(s,4H),0.94-0.84(m,1H). The intermediate 4-[[(1R,2S)-2-(hydroxymethyl)cyclopropyl]buta-1,3-diynyl]benzoic acid (Compound 11) had an ee value of 99.0% and a specific rotation of (c 0.180, CH3 OH)], determination method: accurately weigh the compound, place it in a 10mL volumetric flask, add analytical pure methanol to dissolve, quantify to 10mL scale, and measure it in a Rudolf polarimeter, with the corresponding blank solvent as blank. Compound 11 in this example and compound 11 in Example 4 are both synthesized from (Z)-1,4-butenediol via chiral auxiliary reagents, and the two are enantiomers of each other, with opposite signs and similar values ​​of specific rotation. Compound 11 in Example 4 is confirmed to be (1S, 2R) configuration by circular dichroism, and compound 11 in this example is (1R, 2S) configuration. Example 4 Synthesis of N-(S)-3-amino-1-hydroxyamino-3-methyl-1-oxobutane-2-yl-4-[[(1S,2R)-2-(methoxymethylene)cyclopropyl]buta-1,3-diynyl]benzamide (Compound Id) The preparation method is the same as that of Example 2, except that the raw material cis-2-butene-1,4-diol replaces trans-2-butene-1,4-diol, and the chemical resolution chiral reagent is D-(-)-diisopropyl tartarate. The purity of compound Id is 98%. LCMS-ESI(m / z):384.3[M+H] + . 1 H NMR (500 MHz, DMSO-d 6 ): δ8.12(s,1H),7.85(d,J=8.0Hz,2H),7.61(d,J=8.0Hz,2H),4.28(s,1H),3.34(dd,J=10.6,5.4Hz,1H),3 .24(s,3H),3.15(dd,J=10.7,6.6Hz,1H),1.57-1.48(m,2H),1.09(s,3H),1.01(s,4H),0.94-0.84(m,1H). The intermediate 4-[[(1S,2R)-2-(hydroxymethyl)cyclopropyl]butane-1,3-diynyl]benzoic acid (Compound 11) had an ee value of 98.8% and a specific rotation of (c 0.590, CH 3OH)], determination method: accurately weigh the compound, place it in a 10mL volumetric flask, add analytical pure methanol to dissolve, quantify to 10mL scale, and determine it in a Rudolf polarimeter, with the corresponding blank solvent as blank. At the same time, determine its configuration according to the circular dichroism determination method of compound 8 in the preparation process of Ia: theoretically produce positive chirality. Circular dichroism determination (ECCD) uses a Japanese JASCO J-815 circular dichroism spectrometer to measure the spectrum of 200-400nm at room temperature. The concentration of the measured sample is 0.083% (w / v, methanol), the sample cup light diameter is 10mm, the bandwidth is 1.00nm, and the scanning speed is 100nm / min. The ECCD results (shown in Figure 3) are consistent with the chirality produced by the theory, indicating that compound 11 is (1S, 2R) configuration, and its enantiomer compound 11 in Example 3 is (1R, 2S) configuration. Example 5 In vitro antibacterial activity According to the relevant operation specifications of the Clinical Laboratory Standards Institute (CLSI), the drug sensitivity test was performed using the agar dilution method. The 1920 μg / mL drug solution was diluted with sterile water in turn to 960, 480, 240, 120, 60, 30, 15, 7.5, 3.75, 1.88, 0.94, and 0.47 μg / mL dilutions, and then 1 mL of the dilutions of different concentrations were taken in a plate, and 14 mL of melted MH agar medium was added and mixed. The final concentrations of the drugs in the plate were 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.12, 0.06, and 0.03 μg / mL, respectively, and the agar was solidified for use. The test bacteria were cultured in broth. Before inoculation, the culture solution was adjusted to a McFarland turbidity of 0.5 (approximately 1-2×10 8 CFU / mL), and then dilute the 0.5 McBacteria solution 10 times with broth (about 1-2×10 7 CFU / mL). Use a multi-point inoculator to inoculate the above bacterial solution onto a series of plates containing different drug concentrations (the amount of inoculation bacteria at each inoculation point is about 10 4 CFU), and then cultured at 35°C for 18 hours and observed the results. The minimum concentration of the drug contained in the plate with sterile growth was the minimum inhibitory concentration (MIC). The results are shown in Table 1. In Table-1, the compound of formula (A) is the following compound disclosed in Chinese patent application CN110563611A: ACHN-975 is the following compound disclosed in Chinese patent application CN10329878A: Table-1 In vitro antibacterial activity determination of 4 optical isomers and control drugs (MIC: μg / mL) Table-1(Continued) As shown in Table 1, the four optical isomers Ia, Ib, Ic, and Id have strong antibacterial effects on Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Citrobacter freundii, Pantoea agglomerans, Proteus vulgaris, Proteus mirabilis, and Shigella flexneri, including the most serious clinical drug-resistant NDM-1-producing carbapenem-resistant Escherichia coli (CREC, producing NDM-1) and Klebsiella pneumoniae (CRKP, producing NDM-1), which are better than the compound of formula I. Overall, the antibacterial activity is better than that of the same drug ACHN-975, which is equivalent to or better than the commonly used clinical anti-Gram-negative drugs. Among the four optical isomers, Ia and Ic have the strongest antibacterial activity. Example 6 In vivo antibacterial activity Mice were randomly divided into groups according to body weight, 5 mice in each group, regardless of gender. Escherichia coli ATCC BAA2469 (CRE, producing NDM-1) was selected as the infection bacteria. The test bacterial solution was diluted with 5% highly active dry yeast, and 0.5 mL of 100% minimum lethal dose (100% MLD) bacterial solution was injected into the mouse peritoneum. The drug was administered intravenously once 1 hour after infection, and the administration volume was 10 mL / kg. The number of animals surviving in each group was observed within 7 days, and the animal survival rate was calculated. The results are shown in Table-2. Table-2 In vivo antibacterial activity test of four optical isomers and control drugs against mice infected with Escherichia coli ATCC BAA2469 The four optical isomers Ia, Ib, Ic, and Id all have good in vivo antibacterial activity against mice infected with NDM-1-producing carbapenem-resistant Escherichia coli. The survival rates of animals in the 1.4 mg / kg dose group were 80%, 60%, 80%, and 60%, respectively, which were significantly better than the control drug ACHN-975. Ia and Ic have similar in vivo efficacy, which are better than Ib, Id, and the anti-racemic compound. The in vivo antibacterial activity of compound A and ACHN-975 is lower than that of the other compounds. The specific results are shown in Table 1. The survival rate of mice infected with Escherichia coli ATCC BAA2469 in the 1.5 mg / kg dose group of compound A and ACHN-975 is 0% (i.e., the animal mortality rate is 100%). The effective dose of compound A in vivo antibacterial activity is >3 mg / kg, and the effective dose of ACHN-975 in vivo antibacterial activity is >1.5 mg / kg. In order to reflect the in vivo antibacterial activity of each compound, the dosage of compound A and ACHN-975 in this test was set at more than 1.5 mg / kg. The effective dosage of the in vivo antibacterial activity of several other compounds (Ia, Ib, Ic, Id, Ia / Ib racemate, colistin) was below 1.5 mg / kg, so the dosage of these compounds was set between 0.35 and 1.4 mg / kg (<1.5 mg / kg). Example 7 Acute toxicity in mice The experiment involved 20-21g healthy ICR mice, randomly divided into groups, 3 mice per group, regardless of gender. Each compound was administered once via the tail vein, with a dosing volume of 20mL / kg. The animal reactions were observed immediately after administration, and the number of animal deaths was recorded for 1 week, and the mortality rate was calculated. The results are shown in Table 3. Table-3 Acute toxicity of 4 optical isomers and control drugs in mice The initial acute toxicity of the four optical isomers Ia, Ib, Ic, and Id to mice after intravenous injection was lower than that of the control drug ACHN-975. The mortality rates of the Ia, Ib, Ic, Id, and ACHN-975 150 mg / kg groups were 0%, 0%, 33%, 67%, and 100%, respectively. The toxicity of Ia and Ib was similar, weaker than that of Ic and Id. The mortality rate of the Ia / Ib racemate 150 mg / kg group was 100%, which was more toxic than the single isomers Ia and Ib. Example 8 Inhibition of recombinant Escherichia coli LpxC enzyme activity Preparation of recombinant Escherichia coli LpxC enzyme (rLpxC): Take 2 μL of recombinant Escherichia coli LpxC enzyme (6.29 mg / mL) and add 18 μL of distilled water, mix well, take 2 μL and add 1042.4 μL of distilled water, mix well, and prepare a 36 nM working solution. The substrate is UDP-3-O(R-hydroxytetradecanoyl)-N-acetamidoglucose, and the internal standard is UDP-α-DN-Acetylglucosamine Disodium Salt. Mobile phase A: 90% water-10% acetonitrile containing 10 mm ammonium acetate; B: acetonitrile. The compounds were diluted with distilled water to concentrations of 2560, 640, 160, 40, 10, 2.5, 0.625, 0.15625, 0.0390625, 0.009765625, and 0.00244140625 nM. Reaction system: Prepare the corresponding solution according to the table below, place in a 37℃ metal bath, and mix at 300rpm for 10min. After mixing for 10min, add 10μl 250μM substrate to each group to trigger the reaction, place in a 37℃ metal bath, and react at 300rpm for 30min. Stop solution: Take 1.1μL 1mM internal standard and add 2mL acetonitrile, take 1.5mL EP tube, each EP tube Add 100 μL of stop solution. The internal standard concentration in the final 350 μL system is 100 ng / mL. Detection: Add 10 μL of reaction solution to 100 μL of stop solution EP tube, mix well, then add 240 μL of distilled water and mix well, centrifuge at 14000 rpm for 5 min. Take 70 μL of supernatant and add it to liquid mass spectrometer vial, and use API 6500Qtrap liquid mass spectrometer to determine substrates and metabolites. Calculate the half inhibitory concentration (IC) of the four optical isomers and ACHN-975 on rLpxC enzyme 50 ). The results are shown in Table-4. Table-4 Inhibitory activity of 4 optical isomers and control drugs on recombinant Escherichia coli LpxC enzyme The inhibitory activities of the four optical isomers Ia, Ib, Ic, Id and ACHN-975 and Ia / Ib racemate on rLpxC enzyme were similar. Example 9 Vero cell toxicity Take the Vero cells in the logarithmic growth phase, wash them with PBS, add 2 mL of trypsin, incubate them in a 37°C incubator for 2 min to digest the cells, then add 3 mL of 1640 cell culture medium containing 10% FBS to mix and terminate the digestion, transfer all the liquid to a 15 mL centrifuge tube, centrifuge at 800 rpm for 5 min, discard the supernatant, resuspend with 5 mL of 1640 cell culture medium containing 10% FBS, and use a cell counter to measure the cell density. 100 μL, 3 × 10 5 The cells were inoculated at a density of 100 μg / mL in a 96-well plate, with 6 replicates per group, and incubated at 37°C for 4 h to allow the cells to adhere to the plate. The compound was serially diluted two-fold with PBS, and 10 μL of the compound of corresponding concentration was added to the 96-well plate, shaken on a shaker to mix, and placed at 37° C. for 24 h. 10 μL of CCK-8 reagent was added to the 96-well plate, shaken and mixed, placed at 37°C for 2 h, and the absorbance at 450 nm was measured by an ELISA instrument to calculate the inhibition rate of the compound on Vero cells. The results are shown in Table 5. Table-5 Vero cell cytotoxicity of the four optical isomers and the control drug The four optical isomers and ACHN-975, Ia / Ib racemates were not very toxic to Vero cells, and no IC values ​​were determined. 50 (>128μM).

Claims

1. A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, in, R is C 1-6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof, 3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, which is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, 4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, which is a compound represented by any one of the following formulas (Ia) to (Id) or a pharmaceutically acceptable salt thereof, 5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

6. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for preparing an anti-Gram-negative bacteria drug.

7. The method of claim 6, wherein the gram-negative bacteria is one or more selected from the group consisting of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Citrobacter freundii, Pantoea agglomerans, Proteus vulgaris, Proteus mirabilis and Shigella flexneri.

8. A method for preparing the compound represented by the following formula Ia: The method includes any one or more of the following steps: Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Step 7 Step 8 Step 9 Step 10 Step 11 9. The preparation method according to claim 8, wherein an asymmetric inducing agent is used in step 2.

10. A method for preparing a compound represented by the following formula Ib, Ic or Id, The method comprises any one or more of the following steps, wherein Ib uses trans-2-butene-1,4-diol as a starting material, and formulas Ic and Id use cis-2-butene-1,4-diol as a starting material: Step 1' Step 2' Step 3' Step 4' Step 5' Step 6' Step 7' Step 8' Step 9' Step 10' Step 11' Step 12' Step 13' Step 14'.

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